Recent advances in regulating the cell cycle through inhibiting CDKs for cancer treatment

Abstract

The inhibition of cyclin-dependent kinases (CDKs) is considered a promising strategy for cancer treatment due to their role in cell cycle regulation. However, CDK inhibitors with no selectivity among CDK families have not been approved. A CDK inhibitor with high selectivity for CDK4/6 exhibited significant treatment effects on breast cancer and has become a heavy bomb on the market. Subsequently, resistance gradually decreased the efficacy of selective CDK4/6 inhibitors in breast cancer treatment. In this review, we first introduce the development of selective CDK4/6 inhibitors and then explain the role of CDK2 activation in inducing resistance to CDK4/6 inhibitors. Moreover, we focused on the development of CDK2/4/6 inhibitors and selective CDK2 inhibitors, which will aid in the discovery of novel CDK inhibitors targeting the cell cycle in the future.

Keywords

Cell cycle / Cyclin-dependent kinase (CDK) / CDK inhibitor / Resistance

References

[1] Asghar U, Witkiewicz AK, Turner NC, et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015; 14:130-146. https://doi.org/10.1038/nrd4504.

[2] Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009; 9:153-166. https://doi.org/10.1038/nrc2602.

[3] Zhang M, Zhang L, Hei R, et al. CDK inhibitors in cancer therapy, an overview of recent development. Am J Cancer Res. 2021;11:1913-1935.

[4] O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016; 13:417-430. https://doi.org/10.1038/nrclinonc.2016.26.

[5] Dhillon S.Palbociclib: first global approval. Drugs. 2015; 75:543-551. https://doi.org/10.1007/s40265-015-0379-9.

[6] Goel S, Bergholz JS, Zhao JJ. Targeting CDK4 and CDK6 in cancer. Nat Rev Cancer. 2022; 22:356-372. https://doi.org/10.1038/s41568-022-00456-3.

[7] Morrison L, Loibl S, Turner NC. The CDK4/6 inhibitor revolution — a game-changing era for breast cancer treatment. Nat Rev Clin Oncol. 2024; 21:89-105. https://doi.org/10.1038/s41571-023-00840-4.

[8] Cetin B, Wabl CA, Gumusay O. CDK4/6 inhibitors: mechanisms of resistance and potential biomarkers of responsiveness in breast cancer. Future Oncol. 2022; 18:1143-1157. https://doi.org/10.2217/fon-2021-0842.

[9] Huang J, Zheng L, Sun Z, et al. CDK4/6 inhibitor resistance mechanisms and treatment strategies (Review). Int J Mol Med. 2022;50:128. https://doi.org/10.3892/ijmm.2022.5184.

[10] Lloyd MR, Spring LM, Bardia A, et al. Mechanisms of resistance to CDK4/6 blockade in advanced hormone receptor-positive, HER2-negative breast cancer and emerging therapeutic opportunities. Clin Cancer Res. 2022; 28:821-830. https://doi.org/10.1158/1078-0432.CCR-21-2947.

[11] Fassl A, Geng Y, Sicinski P. CDK4 and CDK6 kinases: From basic science to cancer therapy. Science. 2022;375:eabc1495. https://doi.org/10.1126/science.abc1495.

[12] Gerosa R, De Sanctis R, Jacobs F, et al. Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions. Crit Rev Oncol Hemat. 2024;196:104324. https://doi.org/10.1016/j.critrevonc.2024.104324.

[13] Nurse P, Masui Y, Hartwell L.Understanding the cell cycle. Nat Med. 1998; 4:1103-1106. https://doi.org/10.1038/2594.

[14] Bai J, Li Y, Zhang G. Cell cycle regulation and anticancer drug discovery. Cancer Biol Med. 2017; 14:348-362. https://doi.org/10.20892/j.issn.2095-3941.2017.0033.

[15] Nurse P. Cyclin dependent kinases and cell cycle control (nobel lecture). Chembiochem. 2002; 3:596-603 https://doi.org/10.1002/1439-7633(20020703)3:7<596::AID-CBIC596>3.0.CO;2-.

[16] Pavletich NP. Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J Mol Biol. 1999; 287:821-828. https://doi.org/10.1006/jmbi.1999.2640.

[17] Sherr CJ. D-type cyclins. Trends Biochem Sci. 1995; 20:187-190. https://doi.org/10.1016/S0968-0004(00)89005-2.

[18] Diehl JA.Cycling to cancer with cyclin D1. Cancer Biol Ther. 2002; 1:226-231. https://doi.org/10.4161/cbt.72.

[19] Baldin V, Lukas J, Marcote MJ, et al. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993; 7:812-821. https://doi.org/10.1101/gad.7.5.812.

[20] Goodrich DW, Wang NP, Qian YW, et al. The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle. Cell. 1991; 67:293-302. https://doi.org/10.1016/0092-8674(91)90181-W.

[21] Harbour JW, Luo RX, Santi AD, et al.Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell. 1999; 98:859-869. https://doi.org/10.1016/S0092-8674(00)81519-6.

[22] Pagano M, Draetta G, Jansen-Dürr P. Association of CDK 2 kinase with the transcription factor E2F during S phase. Science. 1992; 255:1144-1147. https://doi.org/10.1126/science.1312258.

[23] Devoto SH, Mudryj M, Pines J, et al. A cyclin A-protein kinase complex possesses sequence-specific DNA binding activity: p33cdk2 is a component of the E2F-cyclin A complex. Cell. 1992; 68:167-176. https://doi.org/10.1016/0092-8674(92)90215-X.

[24] Dubey R, Makhija R, Sharma A, et al. Unveiling the promise of pyrimidine-modified CDK inhibitors in cancer treatment. Bioorg Chem. 2024;149:107508. https://doi.org/10.1016/j.bioorg.2024.107508.

[25] Cavalu S, Abdelhamid AM, Saber S, et al. Cell cycle machinery in oncology: A comprehensive review of therapeutic targets. FASEB J. 2024;38:e23734. https://doi.org/10.1096/fj.202400769R.

[26] Peng C, Zeng W, Su J, et al. Cyclin-dependent kinase 2 (CDK2) is a key mediator for EGF-induced cell transformation mediated through the ELK4/c-Fos signaling pathway. Oncogene. 2016; 35:1170-1179. https://doi.org/10.1038/onc.2015.175.

[27] Ding L, Cao J, Lin W, et al. The Roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer. Int J Mol Sci. 2020;21:1960. https://doi.org/10.3390/ijms21061960.

[28] Lashen A, Alqahtani S, Shoqafi A, et al. Clinicopathological significance of cyclin-dependent kinase 2 (CDK2) in ductal carcinoma in situ and early-stage invasive breast cancers. Int J Mol Sci. 2024;25:5053. https://doi.org/10.3390/ijms25095053.

[29] Malumbres M. Cyclin-dependent kinases. Genome Biol. 2014;15:122. https://doi.org/10.1186/gb4184.

[30] Massacci G, Perfetto L, Sacco F. The cyclin-dependent kinase 1: more than a cell cycle regulator. Br J Cancer. 2023; 129:1707-1716. https://doi.org/10.1038/s41416-023-02468-8.

[31] Diril MK, Ratnacaram CK, Padmakumar VC, et al. Cyclin-dependent kinase 1 (CDK1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration. Proc Natl Acad Sci USA. 2012; 109:3826-3831. https://doi.org/10.1073/pnas.1115201109.

[32] Lima JT, Ferreira JG. Mechanobiology of the nucleus during the G2-M transition. Nucleus. 2024;15:2330947. https://doi.org/10.1080/19491034.2024.2330947.

[33] Parker LL, Piwnica-Worms H. Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase. Science. 1992; 257:1955-1957. https://doi.org/10.1126/science.1384126.

[34] Knight GL, Turnell AS, Roberts S. Role for WEE1 in inhibition of G₂-to-M transition through the cooperation of distinct human papillomavirus type 1 E 4 proteins. J Virol. 2006; 80:7416-7426. https://doi.org/10.1128/JVI.00196-06.

[35] Chow JPH, Poon RYC. The CDK 1 inhibitory kinase Myt1 in DNA damage checkpoint recovery. Oncogene. 2013; 32:4778-4788. https://doi.org/10.1038/onc.2012.504.

[36] Liu F, Stanton JJ, Wu Z, et al. The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex. Mol Cell Biol. 1997; 17:571-583. https://doi.org/10.1128/MCB.17.2.571.

[37] Yan J, Zhuang L, Wang Y, et al.Inhibitors of cell cycle checkpoint target Wee1 kinase - A patent review (2003-2022). Expert Opin Ther Pat. 2022; 32:1217-1244. https://doi.org/10.1080/13543776.2022.2166827.

[38] Kolloch L, Kreinest T, Meisterernst M, et al. Control of expression of key cell cycle enzymes drives cell line-specific functions of CDK7 in human PDAC cells. Int J Mol Sci. 2022;23:812. https://doi.org/10.3390/ijms23020812.

[39] Wilson GA, Vuina K, Sava G, et al. Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition. Mol Cell. 2023;83:4078-4092. e6.

[40] Sava GP, Fan H, Coombes RC, et al. CDK7 inhibitors as anticancer drugs. Cancer Metastasis Rev. 2020; 39:805-823. https://doi.org/10.1007/s10555-020-09885-8.

[41] Airik R, Airik M, Schueler M, et al. Roscovitine blocks collecting duct cyst growth in Cep164-deficient kidneys. Kidney Int. 2019; 96:320-326. https://doi.org/10.1016/j.kint.2019.04.014.

[42] Meijer L, Hery-Arnaud G, Leven C, et al. Safety and pharmacokinetics of Roscovitine (Seliciclib) in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa, a randomized, placebo-controlled study. J Cyst Fibros. 2022; 21:529-536. https://doi.org/10.1016/j.jcf.2021.10.013.

[43] Bose P, Simmons GL, Grant S. Cyclin-dependent kinase inhibitor therapy for hematologic malignancies. Expert Opin Investig Drugs. 2013; 22:723-738. https://doi.org/10.1517/13543784.2013.789859.

[44] Parry D, Guzi T, Shanahan F, et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010; 9:2344-2353. https://doi.org/10.1158/1535-7163.MCT-10-0324.

[45] Sedlacek H, Czech J, Naik R, et al. Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. Int J Oncol. 1996;9:1143-1168.

[46] Joshi KS, Rathos MJ, Joshi RD, et al.In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. Mol Cancer Ther. 2007; 6:918-925. https://doi.org/10.1158/1535-7163.MCT-06-0613.

[47] Byth KF, Thomas A, Hughes G, et al. AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. Mol Cancer Ther. 2009; 8:1856-1866. https://doi.org/10.1158/1535-7163.MCT-08-0836.

[48] Tong W-G, Chen R, Plunkett W, et al. Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J Clin Oncol. 2010; 28:3015-3022. https://doi.org/10.1200/JCO.2009.26.1347.

[49] DePinto W, Chu XJ, Yin X, et al. In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials. Mol Cancer Ther. 2006;5:2644-2658.

[50] Reck M, Horn L, Novello S, et al. Phase II study of roniciclib in combination with cisplatin/etoposide or carboplatin/etoposide as first-line therapy in patients with extensive-disease small cell lung cancer. J Thorac Oncol. 2019; 14:701-711. https://doi.org/10.1016/j.jtho.2019.01.010.

[51] Boss DS, Schwartz GK, Middleton MR, et al. Safety tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours. Ann Oncol. 2010; 21:884-894. https://doi.org/10.1093/annonc/mdp377.

[52] Kouroukis CT, Belch A, Crump M, et al. Flavopiridol in untreated or relapsed mantle-cell lymphoma: results of a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003; 21:1740-1745. https://doi.org/10.1200/JCO.2003.09.057.

[53] Le Tourneau C, Faivre S, Laurence V, et al. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer. 2010; 46:3243-3250. https://doi.org/10.1016/j.ejca.2010.08.001.

[54] Stephenson JJ, Nemunaitis J, Joy AA, et al. Randomized phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer. Lung Cancer. 2014; 83:219-223. https://doi.org/10.1016/j.lungcan.2013.11.020.

[55] Mita MM, Joy AA, Mita A, et al. Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer. Clin Breast Cancer. 2014; 14:169-176. https://doi.org/10.1016/j.clbc.2013.10.016.

[56] Cassaday RD, Goy A, Advani S, et al.A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety ofP276-00, a cyclin-dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2015; 15:392-397. https://doi.org/10.1016/j.clml.2015.02.021.

[57] Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006; 24:1770-1783. https://doi.org/10.1200/JCO.2005.03.7689.

[58] Nemunaitis JJ, Small KA, Kirschmeier P, et al. A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies. J Transl Med. 2013;11:259. https://doi.org/10.1186/1479-5876-11-259.

[59] Ghia P, Scarfò L, Perez S, et al. Efficacy and safety of dinaciclib vs ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia. Blood. 2017; 129:1876-1878. https://doi.org/10.1182/blood-2016-10-748210.

[60] Raje N, Hideshima T, Mukherjee S, et al.Preclinical activity ofP276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma. Leukemia. 2009; 23:961-970. https://doi.org/10.1038/leu.2008.378.

[61] Corona SP, Ravelli A, Cretella D, et al. CDK4/6 inhibitors in HER2-positive breast cancer. Crit Rev Oncol Hemat. 2017; 112:208-214. https://doi.org/10.1016/j.critrevonc.2017.02.022.

[62] Lynce F, Shajahan-Haq AN, Swain SM. CDK4/6 inhibitors in breast cancer therapy: Current practice and future opportunities. Pharmacol Therapeut. 2018; 191:65-73. https://doi.org/10.1016/j.pharmthera.2018.06.008.

[63] Syed YY.Ribociclib: First global approval. Drugs. 2017; 77:799-807. https://doi.org/10.1007/s40265-017-0742-0.

[64] Kim ES.Abemaciclib: First global approval. Drugs. 2017; 77:2063-2070. https://doi.org/10.1007/s40265-017-0840-z.

[65] Chen X, Shen K.Dalpiciclib in advanced breast cancer. Lancet Oncol. 2023; 24:578-579. https://doi.org/10.1016/S1470-2045(23)00228-0.

[66] Dhillon S.Trilaciclib: first approval. Drugs. 2021; 81:867-874. https://doi.org/10.1007/s40265-021-01508-y.

[67] Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016; 375:1925-1936. https://doi.org/10.1056/NEJMoa1607303.

[68] Turner NC, Ro J, André F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015; 373:209-219. https://doi.org/10.1056/NEJMoa1505270.

[69] Rugo HS, Finn RS, Diéras V, et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat. 2019; 174:719-729. https://doi.org/10.1007/s10549-018-05125-4.

[70] Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-Positive, advanced breast cancer. N Engl J Med. 2016; 375:1738-1748. https://doi.org/10.1056/NEJMoa1609709.

[71] Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018; 29:1541-1547. https://doi.org/10.1093/annonc/mdy155.

[72] Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022; 386:942-950. https://doi.org/10.1056/NEJMoa2114663.

[73] Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017; 35:3638-3646. https://doi.org/10.1200/JCO.2017.75.6155.

[74] Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5. https://doi.org/10.1038/s41523-018-0097-z.

[75] Zhang P, Zhang Q, Tong Z, et al. Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023; 24:646-657. https://doi.org/10.1016/S1470-2045(23)00172-9.

[76] Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016; 17:425-439. https://doi.org/10.1016/S1470-2045(15)00613-0.

[77] Cristofanilli M, Rugo HS, Im S-A, et al. Overall survival with palbociclib and fulvestrant in women with HR+/HER2- ABC: updated exploratory analyses of PALOMA-3, a double-blind, phase III randomized study. Clin Cancer Res. 2022; 28:3433-3442. https://doi.org/10.1158/1078-0432.CCR-22-0305.

[78] Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018; 36:2465-2472. https://doi.org/10.1200/JCO.2018.78.9909.

[79] Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020; 382:514-524. https://doi.org/10.1056/NEJMoa1911149.

[80] Sledge GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017; 35:2875-2884. https://doi.org/10.1200/JCO.2017.73.7585.

[81] Sledge GW, Toi M, Neven P, et al. The Effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial. JAMA Oncol. 2020;6:116. https://doi.org/10.1001/jamaoncol.2019.4782.

[82] Xu B, Zhang Q, Zhang P, et al. Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial. Nat Med. 2021; 27:1904-1909. https://doi.org/10.1038/s41591-021-01562-9.

[83] Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a phase ii study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer. Clin Cancer Res. 2017; 23:5218-5224. https://doi.org/10.1158/1078-0432.CCR-17-0754.

[84] Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020; 38:3987-3998. https://doi.org/10.1200/JCO.20.02514.

[85] Johnston SRD, Toi M, O’Shaughnessy J, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023; 24:77-90. https://doi.org/10.1016/S1470-2045(22)00694-5.

[86] Tan AR, Wright GS, Thummala AR, et al. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2019; 20:1587-1601. https://doi.org/10.1016/S1470-2045(19)30616-3.

[87] Weiss JM, Csoszi T, Maglakelidze M, et al. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial. Ann Oncol. 2019; 30:1613-1621. https://doi.org/10.1093/annonc/mdz278.

[88] He S, Roberts PJ, Sorrentino JA, et al. Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion. Sci Transl Med. 2017;9:eaal3986. https://doi.org/10.1126/scitranslmed.aal3986.

[89] Pandey K, An H, Kim SK, et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: a review. Int J Cancer. 2019; 145:1179-1188. https://doi.org/10.1002/ijc.32020.

[90] Álvarez-Fernández M, Malumbres M. Mechanisms of sensitivity and resistance to CDK4/6 inhibition. Cancer Cell. 2020; 37:514-529. https://doi.org/10.1016/j.ccell.2020.03.010.

[91] Guarducci C, Bonechi M, Boccalini G, et al. Mechanisms of resistance to CDK4/6 inhibitors in breast cancer and potential biomarkers of response. Breast Care. 2017; 12:304-308. https://doi.org/10.1159/000484167.

[92] Wander SA, Cohen O, Gong X, et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer. Cancer Discov. 2020; 10:1174-1193. https://doi.org/10.1158/2159-8290.CD-19-1390.

[93] Cai Z, Shi Q, Li Y, et al. LncRNA EILA promotes CDK4/6 inhibitor resistance in breast cancer by stabilizing cyclin E1 protein. Sci Adv. 2023;9:eadi3821. https://doi.org/10.1126/sciadv.adi3821.

[94] Navarro-Yepes J, Kettner NM, Rao X, et al. Abemaciclib is effective in palbociclib-resistant hormone receptor-positive metastatic breast cancers. Cancer Res. 2023;83:3264-3283.

[95] Pandey K, Park N, Park K-S, et al. Combined CDK2 and CDK4/6 inhibition overcomes palbociclib resistance in breast cancer by enhancing senescence. Cancers. 2020;12:3566. https://doi.org/10.3390/cancers12123566.

[96] Alves CL, Ehmsen S, Terp MG, et al. Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer. Nat Commun. 2021;12:5112. https://doi.org/10.1038/s41467-021-25422-9.

[97] Al-Qasem AJ, Alves CL, Ehmsen S, et al. Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer. NPJ Precis Oncol. 2022;6:68. https://doi.org/10.1038/s41698-022-00311-6.

[98] Zikry TM, Wolff SC, Ranek JS, et al. Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2- breast tumor cells. Proc Natl Acad Sci USA. 2024;121:e2309261121. https://doi.org/10.1073/pnas.2309261121.

[99] Herrera-Abreu MT, Palafox M, Asghar U, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Research. 2016;76:2301-2313.

[100] Costa C, Wang Y, Ly A, et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer Discov. 2020; 10:72-85. https://doi.org/10.1158/2159-8290.CD-18-0830.

[101] O’Leary B, Cutts RJ, Liu Y, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018; 8:1390-1403. https://doi.org/10.1158/2159-8290.CD-18-0264.

[102] Jansen VM, Bhola NE, Bauer JA, et al. Kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer. Cancer Res. 2017;77:2488-2499.

[103] Turner NC, Liu Y, Zhu Z, et al. Cyclin E 1 expression and palbociclib efficacy in previously treated hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2019; 37:1169-1178. https://doi.org/10.1200/JCO.18.00925.

[104] Vijayaraghavan S, Karakas C, Doostan I, et al. CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. Nat Commun. 2017;8:15916. https://doi.org/10.1038/ncomms15916.

[105] Freeman-Cook KD, Hoffman RL, Behenna DC, et al. Discovery of PF-06873600, a CDK2/4/6 inhibitor for the treatment of cancer. J Med Chem. 2021; 64:9056-9077. https://doi.org/10.1021/acs.jmedchem.1c00159.

[106] Kramer C, Heinisch T, Fligge T, et al. A Consistent Dataset of Kinetic Solubilities for Early‐Phase Drug Discovery. ChemMedChem. 2009; 4:1529-1536. https://doi.org/10.1002/cmdc.200900205.

[107] Waring MJ. Defining optimum lipophilicity and molecular weight ranges for drug candidates—molecular weight dependent lower logD limits based on permeability. Bioorgan Med Chem Lett. 2009; 19:2844-2851. https://doi.org/10.1016/j.bmcl.2009.03.109.

[108] Johnson TW, Dress KR, Edwards M. Using the golden triangle to optimize clearance and oral absorption. Bioorgan Med Chem Lett. 2009; 19:5560-5564. https://doi.org/10.1016/j.bmcl.2009.08.045.

[109] Ling Y, Hao ZY, Liang D, et al. The expanding role of pyridine and dihydropyridine scaffolds in drug design. Drug Des Devel Ther. 2021; 15:4289-4338. https://doi.org/10.2147/DDDT.S329547.

[110] Freeman-Cook K, Hoffman RL, Miller N, et al. Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor. Cancer Cell. 2021;39:1404-1421. e11.

[111] Turner NC, Liu Y, Zhu Z, et al. Abstract CT039: Cyclin E1 (CCNE1) expression associates with benefit from palbociclib in metastatic breast cancer (MBC) in the PALOMA3 trial. Cancer Res. 2018;78:CT039. https://doi.org/10.1158/1538-7445.AM2018-CT039.

[112] Chen L, Yang N, Huang Y, et al. Development and validation of pharmaceutical care barriers scale in Chinese hospitals: a cross-sectional survey. Front Pharmacol. 2023;14:1194901. https://doi.org/10.3389/fphar.2023.1194901.

[113] Li J, Wang H, Hua Y, et al. Progress and challenges of the new conditional approval process in China: a pooled analysis from 2018 to 2021. Clin Ther. 2023; 45:1111-1118. https://doi.org/10.1016/j.clinthera.2023.09.006.

[114] Ruan X, Wang Y, Zhou L, et al. Evaluation of untargeted metabolomic strategy for the discovery of biomarker of breast cancer. Front Pharmacol. 2022;13:894099. https://doi.org/10.3389/fphar.2022.894099.

[115] Wu H, Yao H, He C, et al. Molecular glues modulate protein functions by inducing protein aggregation: A promising therapeutic strategy of small molecules for disease treatment. Acta Pharm Sin B. 2022; 12:3548-3566. https://doi.org/10.1016/j.apsb.2022.03.019.

[116] Zhou T, Sheng Y, Guan H. Cost-effectiveness of Vedolizumab in the treatment of moderate-to-Severe Crohn’s disease in China. Adv Ther. 2021; 38:4233-4245. https://doi.org/10.1007/s12325-021-01806-7.

[117] Hua WQ, Lin J, Peng N, et al. Clinical development success rates for innovative drugs in China. Int J Pharmacol. 2022; 18:1137-1150. https://doi.org/10.3923/ijp.2022.1137.1150.

[118] Yap TA, Elhaddad AM, Grisham RN, et al. First-in-human phase 1/2a study of a potent and novel CDK2-selective inhibitor PF-07104091 in patients (pts) with advanced solid tumors, enriched for CDK4/6 inhibitor resistant HR+/HER2- breast cancer. J Clin Oncol. 2023;41:3010. https://doi.org/10.1200/JCO.2023.41.16_suppl.3010.

[119] Patel MR, Juric D, Henick BS, et al. BLU-222, an oral, potent, and selective CDK2 inhibitor, in patients with advanced solid tumors: Phase I monotherapy dose escalation. J Clin Oncol. 2023;41:3095. https://doi.org/10.1200/JCO.2023.41.16_suppl.3095.

[120] Bisi JE, Sorrentino JA, Roberts PJ, et al. Preclinical characterization of G1T28: A novel CDK4/6 inhibitor for reduction of chemotherapy-induced myelosuppression. Mol Cancer Ther. 2016; 15:783-793. https://doi.org/10.1158/1535-7163.MCT-15-0775.

[121] Dietrich C, Trub A, Ahn A, et al. INX-315, a selective CDK2 inhibitor, induces cell cycle arrest and senescence in solid tumors. Cancer Discov. 2024; 14:446-467. https://doi.org/10.1158/2159-8290.CD-23-0954.

[122] Watts LP, Spencer SL. A highly anticipated selective therapeutic agent against. CDK2: INX-315. Cancer Discov. 2024; 14:386-388. https://doi.org/10.1158/2159-8290.CD-23-1537.

[123] Sokolsky A, Winterton S, Kennedy K, et al. Discovery of 5, 7-dihydro-6H-pyrrolo [2, 3-d] pyrimidin-6-ones as highly selective CDK2 inhibitors. ACS Med Chem Lett. 2022; 13:1797-1804. https://doi.org/10.1021/acsmedchemlett.2c00408.

[124] Hummel JR, Xiao KJ, Yang JC, et al. Discovery of (4-pyrazolyl)-2-aminopyrimidines as potent and selective inhibitors of cyclin-dependent kinase 2. J Med Chem. 2024; 67:3112-3126. https://doi.org/10.1021/acs.jmedchem.3c02287.

[125] Hardcastle IR, Arris CE, Bentley J, et al.N²-substituted O⁶-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2. J Med Chem. 2004; 47:3710-3722. https://doi.org/10.1021/jm0311442.

[126] McInnes C, Wang S, Anderson S, et al. Structural determinants of CDK4 inhibition and design of selective ATP competitive inhibitors. Chem Biol. 2004; 11:525-534. https://doi.org/10.1016/j.chembiol.2004.03.022.

[127] Lücking U, Jautelat R, Krüger M, et al. The lab oddity prevails: discovery of pan‐CDK inhibitor (R)‐S‐cyclopropyl‐S‐(4‐{[4‐{[(1R, 2R)‐2‐hydroxy‐1‐methylpropyl]oxy}‐5‐(trifluoromethyl)pyrimidin‐2‐yl]amino}phenyl)sulfoximide (BAY 1000394) for the treatment of cancer. ChemMedChem. 2013; 8:1067-1085. https://doi.org/10.1002/cmdc.201300096.

[128] Stepan AF, Karki K, McDonald WS, et al. Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors. J Med Chem. 2011; 54:7772-7783. https://doi.org/10.1021/jm200893p.

[129] Wang Y, Zhu J, Liu J Jim, et al.Optimization beyond AMG232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction. Bioorgan Med Chem Lett. 2014; 24:3782-3785. https://doi.org/10.1016/j.bmcl.2014.06.073.

[130] Di Martino RMC, Maxwell BD, Pirali T. Deuterium in drug discovery: progress, opportunities and challenges. Nat Rev Drug Discov. 2023; 22:562-584. https://doi.org/10.1038/s41573-023-00703-8.

[131] William AD, Lee ACH, Goh KC, et al.Discovery of kinase spectrum selective macrocycle (16 E)-14-methyl-20-oxa-5, 7, 14, 26-tetraazatetracyclo[19.3. 1.1(2, 6). 1(8, 12)]heptacosa-1(25), 2(26), 3, 5, 8(27), 9, 11, 16, 21, 23-decaene (SB1317/TG02), a potent inhibitor of cyclin-dependent kinases (CDKs), janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer. J Med Chem. 2012; 55:169-196. https://doi.org/10.1021/jm201112g.

[132] Brasca MG, Amboldi N, Ballinari D, et al. Identification of N, 1,4,4-Tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1 H-pyrazolo[4, 3-h ]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J Med Chem. 2009; 52:5152-5163. https://doi.org/10.1021/jm9006559.

[133] Yao H, Liu J, Xu S, et al. The structural modification of natural products for novel drug discovery. Expert Opin Drug Discov. 2017; 12:121-140. https://doi.org/10.1080/17460441.2016.1272757.

[134] Das B, Baidya ATK, Mathew AT, et al. Structural modification aimed for improving solubility of lead compounds in early phase drug discovery. Bioorgan Med Chem. 2022;56:116614. https://doi.org/10.1016/j.bmc.2022.116614.

[135] Ishikawa M, Hashimoto Y. Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. J Med Chem. 2011; 54:1539-1554. https://doi.org/10.1021/jm101356p.

[136] Lu Y, Luo Q, Jia X, et al. Multidisciplinary strategies to enhance therapeutic effects of flavonoids from Epimedii Folium: integration of herbal medicine, enzyme engineering, and nanotechnology. J Pharm Anal. 2023; 13:239-254. https://doi.org/10.1016/j.jpha.2022.12.001.

[137] Musgrove EA, Caldon CE, Barraclough J, et al. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011; 11:558-572. https://doi.org/10.1038/nrc3090.

[138] VanArsdale T, Boshoff C, Arndt KT, et al. Molecular pathways: targeting the cyclin D-CDK4/6 axis for cancer treatment. Clin Cancer Res. 2015; 21:2905-2910. https://doi.org/10.1158/1078-0432.CCR-14-0816.

[139] Roskoski R. Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs. Pharmacol Res. 2019; 139:471-488. https://doi.org/10.1016/j.phrs.2018.11.035.

[140] Whittaker SR, Mallinger A, Workman P, et al. Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol Therapeut. 2017; 173:83-105. https://doi.org/10.1016/j.pharmthera.2017.02.008.

[141] Li M, Wang Y, Li M, et al. Integrins as attractive targets for cancer therapeutics. Acta Pharm Sin B. 2021; 11:2726-2737. https://doi.org/10.1016/j.apsb.2021.01.004.

[142] Xin P, Xu X, Deng C, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol. 2020;80:106210. https://doi.org/10.1016/j.intimp.2020.106210.

[143] Li X, Yang C, Wan H, et al. Discovery and development of pyrotinib: a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer. Eur J Pharm Sci. 2017; 110:51-61. https://doi.org/10.1016/j.ejps.2017.01.021.

[144] Wang Y, Xiong B, Xing S, et al. Medicinal prospects of targeting tyrosinase: A feature review. Curr Med Chem. 2023; 30:2638-2671. https://doi.org/10.2174/0929867329666220915123714.

[145] Gong L, Chen C, Liu X, et al. Hainanolide inhibits the progression of colon cancer via inducing the cell cycle arrest, cell apoptosis and activation of the MAPK signaling pathway. Toxicol Appl Pharmacol. 2022;454:116249. https://doi.org/10.1016/j.taap.2022.116249.

[146] Huang J, Wang X, Dong R, et al. Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a novel, potent, and oral cyclin-dependent kinase inhibitor against haematological malignancies. J Med Chem. 2021; 64:12548-12571. https://doi.org/10.1021/acs.jmedchem.1c00271.

[147] Yuan K, Kuang W, Chen W, et al. Discovery of novel and orally bioavailable CDK 4/6 inhibitors with high kinome selectivity, low toxicity and long-acting stability for the treatment of multiple myeloma. Eur J Med Chem. 2022;228:114024. https://doi.org/10.1016/j.ejmech.2021.114024.

[148] Yuan K, Min W, Wang X, et al. Discovery of novel and selective CDK4/6 inhibitors by pharmacophore and structure-based virtual screening. Future Med Chem. 2020; 12:1121-1136. https://doi.org/10.4155/fmc-2020-0011.

[149] Yuan K, Wang X, Dong H, et al. Selective inhibition of CDK4/6: a safe and effective strategy for developing anticancer drugs. Acta Pharm Sin B. 2021; 11:30-54. https://doi.org/10.1016/j.apsb.2020.05.001.

[150] Chen W, Ji M, Cheng H, et al. Discovery, optimization, and evaluation of selective CDK4/6 inhibitors for the treatment of breast cancer. J Med Chem. 2022; 65:15102-15122. https://doi.org/10.1021/acs.jmedchem.2c00947.

[151] Chen P, Xu Y, Li X, et al. Development and strategies of CDK4/6 inhibitors. Future Med Chem. 2020; 12:127-145. https://doi.org/10.4155/fmc-2019-0062.

[152] Wang Y, Zhi Y, Jin Q, et al. Discovery of 4-((7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-kinase inhibitor with potentially high efficiency against acute myelocytic leukemia. J Med Chem. 2018; 61:1499-1518. https://doi.org/10.1021/acs.jmedchem.7b01261.

[153] Li T, Weng T, Zuo M, et al. Recent progress of cyclin-dependent kinase inhibitors as potential anticancer agents. Future Med Chem. 2016; 8:2047-2076. https://doi.org/10.4155/fmc-2016-0129.

[154] He L, Lu N, Dai Q, et al.Wogonin induced G1 cell cycle arrest by regulating Wnt/β-catenin signaling pathway and inactivating CDK8 in human colorectal cancer carcinoma cells. Toxicology. 2013; 312:36-47. https://doi.org/10.1016/j.tox.2013.07.013.

[155] Zhu J, Cai Y, Kong M, et al. Design, synthesis, and biological evaluation for first GPX4 and CDK dual inhibitors. J Med Chem. 2024; 67:2758-2776. https://doi.org/10.1021/acs.jmedchem.3c01890.

[156] Yang L, Zhang H, Hu R, et al. Wogonin induces G1 phase arrest through inhibiting CDK4 and cyclin D1 concomitant with an elevation in p21Cip1 in human cervical carcinoma HeLa cells. Biochem Cell Biol. 2009; 87:933-942. https://doi.org/10.1139/O09-060.

[157] Lu Y, Sheng X, Liu C, et al. SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer. Pharmacol Res. 2023;190:106731. https://doi.org/10.1016/j.phrs.2023.106731.

[158] Wei Q, Xu Y, Liu W, et al. Cost-effectiveness of abemaciclib plus endocrine therapy in high-risk HR+/HER2-early breast cancer in China. Cost Eff Resour Alloc. 2023;21:91. https://doi.org/10.1186/s12962-023-00499-9.

[159] Zhang Y, Zhao G, Yu L, et al. Heat-shock protein 90α protects NME1 against degradation and suppresses metastasis of breast cancer. Br J Cancer. 2023; 129:1679-1691. https://doi.org/10.1038/s41416-023-02435-3.

[160] Li J, Zhou J, Wang H, et al.Trends in disparities and transitions of treatment in patients with early breast cancer in China and the US, 2011 to 2021. JAMA Netw Open. 2023;6:e2321388. https://doi.org/10.1001/jamanetworkopen.2023.21388.

[161] Qiao YW, Yu G, Li GF. Overall survival benefit with sacituzumab govitecan in metastatic breast cancer: a post hoc interaction analyses of a randomized controlled trail. Clin Drug Investig. 2024; 44:455-457. https://doi.org/10.1007/s40261-024-01367-x.

[162] Yang YH, Liu JW, Lu C, et al. CAR-T cell therapy for breast cancer: from basic research to clinical application. Int J Biol Sci. 2022; 18:2609-2626. https://doi.org/10.7150/ijbs.70120.

[163] Wang T, You Q, Huang F, et al. Recent advances in selective estrogen receptor modulators for breast cancer. Mini Rev Med Chem. 2009; 9:1191-1201. https://doi.org/10.2174/138955709789055207.

[164] Witkiewicz AK, Knudsen ES. Retinoblastoma tumor suppressor pathway in breast cancer: prognosis, precision medicine, and therapeutic interventions. Breast Cancer Res. 2014;16:3396.

[165] Guan Q, Gao Z, Chen Y, et al. Structural modification strategies of triazoles in anticancer drug development. Eur J Med Chem. 2024;275:116578. https://doi.org/10.1016/j.ejmech.2024.116578.

[166] Dong RF, Zhu ML, Liu MM, et al. EGFR mutation mediates resistance to EGFR tyrosine kinase inhibitors in NSCLC: from molecular mechanisms to clinical research. Pharmacol Res. 2021;167:105583. https://doi.org/10.1016/j.phrs.2021.105583.

[167] Liu Y, Chen Y, Jiang J, et al. Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer. Eur J Med Chem. 2023;247:115013. https://doi.org/10.1016/j.ejmech.2022.115013.

[168] Li Y, Liu R, Han X, et al. PLAGL2 increases adriamycin resistance and EMT in breast cancer cells by activating the Wnt pathway. Genes Genom. 2023; 45:49-57. https://doi.org/10.1007/s13258-022-01330-0.

[169] Yang J, Yu YC, Wang ZX, et al. Research strategies of small molecules as chemotherapeutics to overcome multiple myeloma resistance. Eur J Med Chem. 2024;271:116435. https://doi.org/10.1016/j.ejmech.2024.116435.

[170] Qin M, Xin Y, Bian Y, et al. Phosphorylation-induced ubiquitination and degradation of PXR through CDK2-TRIM21 axis. Cells. 2022;11:264. https://doi.org/10.3390/cells11020264.

[171] Qian X, Dai X, Luo L, et al. An interpretable multitask framework BiLAT enables accurate prediction of cyclin-dependent protein kinase inhibitors. J Chem Inf Model. 2023; 63:3350-3368. https://doi.org/10.1021/acs.jcim.3c00473.

[172] Tadesse S, Anshabo AT, Portman N, et al. Targeting CDK 2 in cancer: challenges and opportunities for therapy. Drug Discov Today. 2020; 25:406-413. https://doi.org/10.1016/j.drudis.2019.12.001.

[173] Arora M, Moser J, Hoffman TE, et al. Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity. Cell. 2023;186:2628-2643. e21.

[174] Cai W, Tong R, Sun Y, et al. Comparative efficacy of five approved Janus kinase inhibitors as monotherapy and combination therapy in patients with moderate-to-severe active rheumatoid arthritis: a systematic review and network meta-analysis of randomized controlled trials. Front Pharmacol. 2024;15:1387585. https://doi.org/10.3389/fphar.2024.1387585.

[175] Roy D, Sheng GY, Herve S, et al. Interplay between cancer cell cycle and metabolism: challenges, targets and therapeutic opportunities. Biomed Pharmacother. 2017; 89:288-296. https://doi.org/10.1016/j.biopha.2017.01.019.

[176] Xiong S, Song K, Xiang H, et al. Dual-target inhibitors based on ERα: Novel therapeutic approaches for endocrine resistant breast cancer. Eur J Med Chem. 2024;270:116393. https://doi.org/10.1016/j.ejmech.2024.116393.

[177] Chen X, He R, Chen X, et al. Optimizing dose-schedule regimens with bayesian adaptive designs: opportunities and challenges. Front Pharmacol. 2023;14:1261312. https://doi.org/10.3389/fphar.2023.1261312.

[178] Sun Y, Yu X, Wang X, et al. Bispecific antibodies in cancer therapy: target selection and regulatory requirements. Acta Pharm Sin B. 2023; 13:3583-3597. https://doi.org/10.1016/j.apsb.2023.05.023.

[179] Xiang Y, Liu X, Wang Y, et al. Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges. Front Immunol. 2024;15:1366260. https://doi.org/10.3389/fimmu.2024.1366260.

[180] Li Y, Li X, Zhu M, et al. Development of a physiologically based pharmacokinetic population model for diabetic patients and its application to understand disease-drug-drug interactions. Clin Pharmacokinet. 2024;63:831- 845 https://doi.org/10.1007/s40262-024-01383-2.

[181] Chen Y, Xu S, Ren S, et al. Design of a targeted dual drug delivery system for boosting the efficacy of photoimmunotherapy against melanoma proliferation and metastasis. J Adv Res. 2024;S2090- 1232(24)00207-8. https://doi.org/10.1016/j.jare.2024.05.017.

[182] Krebs MG, Lord S, Kenny L, et al. 230MO First in human, modular study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced solid malignancies. Ann Oncol. 2021;32:S458.

[183] Coombes C, Howell SJ, Krebs MG, et al.AbstractGS3-10: study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in combination with fulvestrant in patients with advanced hormone receptor positive HER2 negative breast cancer (HR + BC). Cancer Res. 2022;82:GS3.

[184] Coombes RC, Howell S, Lord SR, et al. Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib. Nat Commun. 2023;14:4444. https://doi.org/10.1038/s41467-023-40061-y.

[185] Wang M, Wang T, Zhang X, et al. Cyclin-dependent kinase 7 inhibitors in cancer therapy. Future Med Chem. 2020; 12:813-833. https://doi.org/10.4155/fmc-2019-0334.

[186] Wander SA, Han HS, Zangardi ML, et al. Clinical outcomes with abemaciclib after prior CDK4/6 inhibitor progression in breast cancer: A multicenter experience. J Natl Compr Canc Netw. 2021;24:1-8.

[187] Yao T, Xiao H, Wang H, et al. Recent advances in PROTACs for drug targeted protein research. Int J Mol Sci. 2022;23:10328. https://doi.org/10.3390/ijms231810328.

[188] Wang Y, Jiang X, Feng F, et al. Degradation of proteins by PROTACs and other strategies. Acta Pharm Sin B. 2020; 10:207-238. https://doi.org/10.1016/j.apsb.2019.08.001.

[189] Xie S, Zhu J, Li J, et al. Small-molecule hydrophobic tagging: a promising strategy of druglike technology for targeted protein degradation. J Med Chem. 2023; 66:10917-10933. https://doi.org/10.1021/acs.jmedchem.3c00736.

[190] Ma S, Ji J, Tong Y, et al. Non-small molecule PROTACs (NSM-PROTACs): protein degradation kaleidoscope. Acta Pharm Sin B. 2022; 12:2990-3005. https://doi.org/10.1016/j.apsb.2022.02.022.

[191] Hua L, Zhang Q, Zhu X, et al. Beyond proteolysis-targeting chimeric molecules: designing heterobifunctional molecules based on functional effectors. J Med Chem. 2022; 65:8091-8112. https://doi.org/10.1021/acs.jmedchem.2c00316.

[192] Xue X, Li Q, Zhang P, et al. PET/NIR fluorescence bimodal imaging for targeted tumor detection. Mol Pharm. 2023; 20:6262-6071. https://doi.org/10.1021/acs.molpharmaceut.3c00660.

[193] Wang YW, Lan L, Wang M, et al. PROTACS: A technology with a gold rush-like atmosphere. Eur J Med Chem. 2023;247:115037. https://doi.org/10.1016/j.ejmech.2022.115037.

[194] Zhong Y, Chi F, Wu H, et al. Emerging targeted protein degradation tools for innovative drug discovery: From classical PROTACs to the novel and beyond. Eur J Med Chem. 2022;231:114142. https://doi.org/10.1016/j.ejmech.2022.114142.

[195] Dong X, Sun R, Wang J, et al. Glutathione S-transferases P1-mediated interleukin-6 in tumor-associated macrophages augments drug-resistance in MCF-7 breast cancer. Biochem Pharmacol. 2020;182:114289. https://doi.org/10.1016/j.bcp.2020.114289.

[196] Yang N, Kong B, Zhu Z, et al. Recent advances in targeted protein degraders as potential therapeutic agents. Mol Divers. 2024; 28:309-333. https://doi.org/10.1007/s11030-023-10606-w.

[197] Zhu P, Zhang J, Yang Y, et al. Design, synthesis and biological evaluation of isoxazole-containing biphenyl derivatives as small-molecule inhibitors targeting the programmed cell death-1/ programmed cell death-ligand 1 immune checkpoint. Mol Divers. 2022; 26:245-264. https://doi.org/10.1007/s11030-021-10208-4.

[198] Zhou QQ, Xiao HT, Yang F, et al. Advancing targeted protein degradation for metabolic diseases therapy. Pharmacol Res. 2023;188:106627. https://doi.org/10.1016/j.phrs.2022.106627.

[199] Sang H, Liu J, Zhou F, et al. Target-responsive subcellular catabolism analysis for early-stage antibody-drug conjugates screening and assessment. Acta Pharm Sin B. 2021; 11:4020-4031. https://doi.org/10.1016/j.apsb.2021.05.024.

[200] Wang Y, Rui M, Guan X, et al. Cost-effectiveness analysis of abemaciclib plus fulvestrant in the second-line treatment of women with HR+/HER2- advanced or metastatic breast cancer: A US payer perspective. Front Med. 2021;8:658747. https://doi.org/10.3389/fmed.2021.658747.

[201] Zhang K, Li J, Xin X, et al. Dual targeting of cancer cells and MMPs with self-assembly hybrid nanoparticles for combination therapy in combating cancer. Pharmaceutics. 2021;13:1990. https://doi.org/10.3390/pharmaceutics13121990.

[202] Shao H, Zhao M, Guan AJ, et al. A network meta-analysis of efficacy and safety for first-line and second/further-line therapies in postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer. BMC Med. 2024;22:13. https://doi.org/10.1186/s12916-023-03238-2.

[203] Wang L, Xu X, Jiang Z, et al. Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery. Acta Pharm Sin B. 2020; 10:1904-1925. https://doi.org/10.1016/j.apsb.2020.01.018.

[204] Yu B, Du Z, Zhang Y, et al. Small-molecule degraders of cyclin-dependent kinase protein: a review. Future Med Chem. 2022; 14:167-185. https://doi.org/10.4155/fmc-2021-0154.

[205] Xing S, Li Q, Xiong B, et al. Structure and therapeutic uses of butyrylcholinesterase: Application in detoxification, Alzheimer’s disease, and fat metabolism. Med Res Rev. 2021; 41:858-901. https://doi.org/10.1002/med.21745.

[206] Xiao K, Liu F, Liu J, et al. The effect of metformin on lung cancer risk and survival in patients with type 2 diabetes mellitus: a meta‐analysis. J Clin Pharm Ther. 2020; 45:783-792. https://doi.org/10.1111/jcpt.13167.

[207] He Q, Zhao X, Wu D, et al. Hydrophobic tag-based protein degradation: development, opportunity and challenge. Eur J Med Chem. 2023;260:115741. https://doi.org/10.1016/j.ejmech.2023.115741.

[208] Dorjsuren B, Chaurasiya B, Ye Z, et al. Cetuximab-coated thermo-sensitive liposomes loaded with magnetic nanoparticles and doxorubicin for targeted EGFR-expressing breast cancer combined therapy. Int J Nanomedicine. 2020; 15:8201-8215. https://doi.org/10.2147/IJN.S261671.

[209] Zheng M, Zhang XY, Chen W, et al. Molecules inducing specific cyclin-dependent kinase degradation and their possible use in cancer therapy. Future Med Chem. 2024; 16:369-388. https://doi.org/10.4155/fmc-2023-0259.

[210] Ha S, Luo G, Xiang H. A comprehensive overview of small-molecule androgen receptor degraders: recent progress and future perspectives. J Med Chem. 2022; 65:16128-16154. https://doi.org/10.1021/acs.jmedchem.2c01487.

[211] Tsang WP, Zhang F, He Q, et al. Icaritin enhances mESC self-renewal through upregulating core pluripotency transcription factors mediated by ERα. Sci Rep. 2017;7:40894. https://doi.org/10.1038/srep40894.

[212] Luo P, An Y, He J, et al. Icaritin with autophagy/mitophagy inhibitors synergistically enhances anticancer efficacy and apoptotic effects through PINK1/Parkin-mediated mitophagy in hepatocellular carcinoma. Cancer Lett. 2024;587:216621. https://doi.org/10.1016/j.canlet.2024.216621.