Application of a macrocyclization strategy in kinase inhibitor development

Abstract

Kinases have a pivotal role in phosphorylation and kinase dysregulation has been implicated in the occurrence and progression of various diseases. By mid-2024 the Food and Drug Administration had approved 81 small-molecule kinase inhibitors targeting greater than 30 kinases, providing substantial clinical benefits for patients with cancer and other diseases. However, many reported kinase inhibitors exhibit poor target selectivity, limited solubility, and issues with drug resistance. To address these challenges medicinal chemists have used a macrocyclization strategy to optimize these molecules and three macrocyclic kinase inhibitors (lorlatinib [ALK/ROS1], pacritinib [Flt3/JAK2], and repotrectinib [TRK/ROS1]) have received FDA approval. The macrocyclization strategy is now widely used to enhance kinase inhibitory activity, overcome drug resistance caused by point mutations, improve kinase selectivity, and optimize drug-like properties. In this review we provide a comprehensive overview of the utilization of macrocyclization in the optimization of kinase inhibitors by detailing the structural modification process from lead compounds to macrocyclic molecules that has been applied in recent years. In addition, we discuss the limitations of existing macrocyclic kinase inhibitors and propose key considerations for the development of improved macrocyclic molecules. We aim for this review to offer valuable insights for future advances in kinase inhibitor development.

Keywords

Kinase inhibitor / Macrocyclization strategy / Drug design / Binding affinity / Kinase selectivity / Drug-like properties

References

[1] Fabbro D, Cowan-Jacob SW, Moebitz H: Ten Things You Should Know About Protein Kinases: Iuphar Review 14. British Journal of Pharmacology 2015, 172: 2675-2700.

[2] Du Z, Lovly CM: Mechanisms of Receptor tyrosine Kinase Activation in Cancer. Molecular Cancer 2018, 17: 58.

[3] Roskoski R Jr: A Historical Overview of Protein Kinases and Their Targeted Small Molecule Inhibitors. Pharmacological Research 2015, 100: 1-23.

[4] Glaviano A, Foo ASC, Lam HY, Yap KCH, Jacot W, Jones RH, et al.: PI3K/AKT/mTOR Signaling Transduction Pathway and Targeted Therapies in Cancer. Molecular Cancer 2023, 22: 138.

[5] Roskoski R Jr: Properties of FDA-Approved Small Molecule Protein Kinase Inhibitors: A 2024 Update. Pharmacological Research 2024, 200: 107059.

[6] Smyth LA, Collins I: Measuring and Interpreting the Selectivity of Protein Kinase Inhibitors. Journal of Chemical Biology 2009, 2: 131-151.

[7] Orchard S: Kinases as Targets: Prospects for Chronic Therapy. Current Opinion in Drug Discovery & Development 2002, 5: 713-717.

[8] Wang B, Wu H, Hu C, Wang H, Liu J, Wang W, et al.: An Overview of Kinase Downregulators and Recent Advances in Discovery Approaches. Signal Transduction and Targeted Therapy 2021, 6: 423.

[9] Jansook P, Loftsson T, Stefánsson E: Drug-like Properties of Tyrosine Kinase Inhibitors in Ophthalmology: Formulation and Topical Availability. International Journal of Pharmaceutics 2024, 655: 124018.

[10] Zhou Y, Xiang S, Yang F, Lu X: Targeting Gatekeeper Mutations for Kinase Drug Discovery. Journal of Medicinal Chemistry 2022, 65: 15540-15558.

[11] Lu X, Smaill JB, Ding K: Medicinal Chemistry Strategies for the Development of Kinase Inhibitors Targeting Point Mutations. Journal of Medicinal Chemistry 2020, 63: 10726-10741.

[12] Zhao Z, Bourne PE: Rigid Scaffolds Are Promising for Designing Macrocyclic Kinase Inhibitors. ACS Pharmacology & Translational Science 2023, 6: 1182-1191.

[13] Acharya B, Saha D, Armstrong D, Jabali B, Hanafi M, Herrera-Rueda A, et al.: Kinase Inhibitor Macrocycles: A Perspective on Limiting Conformational Flexibility When Targeting The Kinome with Small Molecules. RSC Medicinal Chemistry 2024, 15: 399-415.

[14] Driggers EM, Hale SP, Lee J, Terrett NK: The Exploration of Macrocycles For Drug Discovery - An Underexploited Structural Class. Nature Reviews Drug Discovery 2008, 7: 608-624.

[15] Bhujbal SP, Hah JM: An Intriguing Purview on the Design of Macrocyclic Inhibitors for Unexplored Protein Kinases Through Their Binding Site Comparison. Pharmaceuticals (Basel, Switzerland) 2023, 16: 1009.

[16] Zhang C, Liu F, Zhang Y, Song C: Macrocycles and Macrocyclization in Anticancer Drug Discovery: Important Pieces of the Puzzle. European Journal of Medicinal Chemistry 2024, 268: 116234.

[17] Mallinson J, Collins I: Macrocycles in New Drug Discovery. Future Medicinal Chemistry 2012, 4: 1409-1438.

[18] Darlami O, Pun R, Ahn SH, Kim SH, Shin D: Macrocyclization Strategy for Improving Candidate Profiles in Medicinal Chemistry. European Journal of Medicinal Chemistry 2024, 272: 116501.

[19] Johnson TW, Richardson PF, Bailey S, Brooun A, Burke BJ, Collins MR, et al.: Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency Against ALK-Resistant Mutations. Journal of Medicinal Chemistry 2014, 57: 4720-4744.

[20] Basit S, Ashraf Z, Lee K, Latif M: First Macrocyclic 3^rd-Generation ALK Inhibitor for Treatment of ALK/ROS1 Cancer: Clinical and Designing Strategy Update of Lorlatinib . European Journal of Medicinal Chemistry 2017, 134: 348-356.

[21] William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, et al.: Discovery of the Macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/fms-like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma. Journal of Medicinal Chemistry 2011, 54: 4638-4658.

[22] Yun MR, Kim DH, Kim SY, Joo HS, Lee YW, Choi HM, et al.: Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer. Clinical Cancer Research 2020, 26: 3287-3295.

[23] Dhillon S: Repotrectinib: First Approval. Drugs 2024, 84: 239-246.

[24] William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, et al.: Discovery of Kinase Spectrum Selective Macrocycle (16E)-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. Journal of Medicinal Chemistry 2012, 55: 169-196.

[25] William AD, Lee AC, Poulsen A, Goh KC, Madan B, Hart S, et al.: Discovery of the Macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a Potent Inhibitor of Janus Kinase 2/fms-like Tyrosine Kinase-3 (JAK2/FLT3) for the Treatment of Rheumatoid Arthritis. Journal of Medicinal Chemistry 2012, 55: 2623-2640.

[26] Shen Y, Boivin R, Yoneda N, Du H, Schiller S, Matsushima T, et al.: Discovery of Anti-Inflammatory Clinical Candidate E6201, Inspired from Resorcylic Lactone LL-Z1640-2, III. Bioorganic & Medicinal Chemistry Letters 2010, 20: 3155-3157.

[27] Malumbres M: Cyclin-dependent Kinases. Genome Biology 2014, 15: 122.

[28] Chou J, Quigley DA, Robinson TM, Feng FY, Ashworth A: Transcription-Associated Cyclin-Dependent Kinases as Targets and Biomarkers for Cancer Therapy. Cancer Discovery 2020, 10: 351-370.

[29] Schwartz GK, Shah MA: Targeting the Cell Cycle: A New Approach to Cancer Therapy. Journal of Clinical Oncology 2005, 23: 9408-9421.

[30] Yuan K, Wang X, Dong H, Min W, Hao H, Yang P: Selective Inhibition of CDK4/6: A Safe and Effective Strategy for Developing Anticancer Drugs. Acta Pharmaceutica Sinica B 2021, 11: 30-54.

[31] Jhaveri K, Burris Rd HA, Yap TA, Hamilton E, Rugo HS, Goldman JW, et al.: The Evolution of Cyclin Dependent Kinase Inhibitors in the Treatment of Cancer. Expert Review of Anticancer Therapy 2021, 21: 1105-1124.

[32] Dhillon S: Trilaciclib: First Approval. Drugs 2021, 81: 867-874.

[33] Yu Y, Huang J, He H, Han J, Ye G, Xu T, et al.: Accelerated Discovery of Macrocyclic CDK2 Inhibitor QR-6401 by Generative Models and Structure-Based Drug Design. ACS Medicinal Chemistry Letters 2023, 14: 297-304.

[34] Arús-Pous J, Patronov A, Bjerrum EJ, Tyrchan C, Reymond JL, Chen H, et al.: SMILES-based Deep Generative Scaffold Decorator for De-Novo Drug Design. Journal of Cheminformatics 2020, 12: 38.

[35] Meng F, Liu J, Cao Z, Yu J, Steurer B, Yang Y, et al.: Discovery of Macrocyclic CDK2/4/6 Inhibitors with Improved Potency and DMPK Properties Through a Highly Efficient Macrocyclic Drug Design Platform. Bioorganic Chemistry 2024, 146: 107285.

[36] Zhang L, Luo B, Lu Y, Chen Y: Targeting Death-Associated Protein Kinases for Treatment of Human Diseases: Recent Advances and Future Directions. Journal of Medicinal Chemistry 2023, 66: 1112-1136.

[37] Farag AK, Roh EJ: Death-associated Protein Kinase (DAPK) Family Modulators: Current and Future Therapeutic Outcomes. Medicinal Research Reviews 2019, 39: 349-385.

[38] Kurz CG, Preuss F, Tjaden A, Cusack M, Amrhein JA, Chatterjee D, et al.: Illuminating the Dark: Highly Selective Inhibition of Serine/Threonine Kinase 17A with Pyrazolo[1,5-a]pyrimidine-Based Macrocycles. Journal of Medicinal Chemistry 2022, 65: 7799-7817.

[39] Krämer A, Kurz CG, Berger BT, Celik IE, Tjaden A, Greco FA, et al.: Optimization of pyrazolo[1,5-a]pyrimidines Lead to the Identification of a Highly Selective Casein Kinase 2 Inhibitor. European Journal of Medicinal Chemistry 2020, 208: 112770.

[40] Walte A, Rüben K, Birner-Gruenberger R, Preisinger C, Bamberg-Lemper S, Hilz N, et al.: Mechanism of Dual Specificity Kinase Activity of DYRK1A. The FEBS Journal 2013, 280: 4495-4511.

[41] Becker W, Sippl W: Activation, Regulation, and Inhibition of DYRK1A. The FEBS Journal 2011, 278: 246-256.

[42] Liu T, Wang Y, Wang J, Ren C, Chen H, Zhang J: DYRK1A Inhibitors for Disease Therapy: Current Status and Perspectives. European Journal of Medicinal Chemistry 2022, 229: 114062.

[43] Czarna A, Wang J, Zelencova D, Liu Y, Deng X, Choi HG, et al.: Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) Inhibitors. Journal of Medicinal Chemistry 2018, 61: 7560-7572.

[44] Jarhad DB, Mashelkar KK, Kim HR, Noh M, Jeong LS: Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors as Potential Therapeutics. Journal of Medicinal Chemistry 2018, 61: 9791-9810.

[45] Powell CE, Hatcher JM, Jiang J, Vatsan PS, Che J, Gray NS: Selective Macrocyclic Inhibitors of DYRK1A/B. ACS Medicinal Chemistry Letters 2022, 13: 577-585.

[46] Daver N, Schlenk RF, Russell NH, Levis MJ: Targeting FLT3 Mutations in AML: Review of Current Knowledge and Evidence. Leukemia 2019, 33: 299-312.

[47] Zhao JC, Agarwal S, Ahmad H, Amin K, Bewersdorf JP, Zeidan AM: A Review of FLT3 Inhibitors in Acute Myeloid Leukemia. Blood Reviews 2022, 52: 100905.

[48] Larrosa-Garcia M, Baer MR: FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions. Molecular Cancer Therapeutics 2017, 16: 991-1001.

[49] Isidori A, Visani G, Ferrara F: FMS-like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia. Current Opinion in Oncology 2023, 35: 589-593.

[50] Eguchi M, Minami Y, Kuzume A, Chi S: Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia. Biomedicines 2020, 8: 245.

[51] Zheng X, Chen Z, Guo M, Liang H, Song X, Liu Y, et al.: Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives as FMS-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations. ACS Pharmacology & Translational Science 2024, 7: 1485-1506.

[52] Lee HK, Kim HW, Lee IY, Lee J, Lee J, Jung DS, et al.: G-749, a Novel FLT3 Kinase Inhibitor, can Overcome Drug Resistance for the Treatment of Acute Myeloid Leukemia. Blood 2014, 123: 2209-2219.

[53] Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G: Targeting MET in Cancer: Rationale and Progress. Nature Reviews Cancer 2012, 12: 89-103.

[54] Teng L, Lu J: cMET as a Potential Therapeutic Target in Gastric Cancer (Review). International Journal of Molecular Medicine 2013, 32: 1247-1254.

[55] Trusolino L, Bertotti A, Comoglio PM: MET Signalling: Principles and Functions in Development, Organ Regeneration and Cancer. Nature Reviews Molecular Cell Biology 2010, 11: 834-848.

[56] Remon J, Hendriks LEL, Mountzios G, García-Campelo R, Saw SPL, Uprety D, et al.: MET Alterations in NSCLC-Current Perspectives and Future Challenges. Journal of Thoracic Oncology 2023, 18: 419-435.

[57] Fu J, Su X, Li Z, Deng L, Liu X, Feng X, et al.: HGF/c-MET Pathway in Cancer: From Molecular Characterization to Clinical Evidence. Oncogene 2021, 40: 4625-4651.

[58] Kuniyasu H, Yasui W, Kitadai Y, Yokozaki H, Ito H, Tahara E: Frequent Amplification of the c-met Gene in Scirrhous Type Stomach Cancer. Biochemical and Biophysical Research Communications 1992, 189: 227-232.

[59] Recondo G, Che J, Jänne PA, Awad MM: Targeting MET Dysregulation in Cancer. Cancer Discovery 2020, 10: 922-934.

[60] Wang C, Li J, Qu L, Tang X, Song X, Yang F, et al.: Discovery of D6808, a Highly Selective and Potent Macrocyclic c-Met Inhibitor for Gastric Cancer Harboring MET Gene Alteration Treatment. Journal of Medicinal Chemistry 2022, 65: 15140-15164.

[61] Dorsch D, Schadt O, Stieber F, Meyring M, Grädler U, Bladt F, et al.: Identification and Optimization of Pyridazinones as Potent and Selective c-Met Kinase Inhibitors. Bioorganic & Medicinal Chemistry Letters 2015, 25: 1597-1602.

[62] Tiedt R, Degenkolbe E, Furet P, Appleton BA, Wagner S, Schoepfer J, et al.: A Drug Resistance Screen Using a Selective Met Inhibitor Reveals a Spectrum of Mutations that Partially Overlap with Activating Mutations Found in Cancer Patients. Cancer Research 2011, 71: 5255-5264.

[63] Singh F, Ganley IG: Parkinson’s Disease and Mitophagy: An Emerging Role for LRRK2. Biochemical Society Transactions 2021, 49: 551-562.

[64] Santpere G, Ferrer I: LRRK2 and Neurodegeneration. Acta Neuropathologica 2009, 117: 227-246.

[65] Boecker CA, Goldsmith J, Dou D, Cajka GG, Holzbaur ELF: Increased LRRK2 Kinase Activity Alters Neuronal Autophagy by Disrupting the Axonal Transport of Autophagosomes. Current Biology 2021, 31: 2140-2154.e6.

[66] Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, et al.: Phenotype, Genotype, and Worldwide Genetic Penetrance of LRRK2-associated Parkinson’s Disease: A Case-control Study. The Lancet Neurology 2008, 7: 583-590.

[67] Hu J, Zhang D, Tian K, Ren C, Li H, Lin C, et al.: Small-molecule LRRK2 Inhibitors for PD Therapy: Current Achievements and Future Perspectives. European Journal of Medicinal Chemistry 2023, 256: 115475.

[68] Kramer T, Lo Monte F, Göring S, Okala Amombo GM, Schmidt B: Small Molecule Kinase Inhibitors for LRRK2 and Their Application to Parkinson’s Disease Models. ACS Chemical Neuroscience 2012, 3: 151-160.

[69] Kim K, Jang A, Shin H, Ye I, Lee JE, Kim T, et al.: Concurrent Optimizations of Efficacy and Blood-Brain Barrier Permeability in New Macrocyclic LRRK2 Inhibitors for Potential Parkinson’s Disease Therapeutics. Journal of Medicinal Chemistry 2024, 67: 7647-7662.

[70] Mishra R, Patel H, Alanazi S, Kilroy MK, Garrett JT: PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. International Journal of Molecular Sciences 2021, 22: 3464.

[71] Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X: Targeting PI3K in Cancer: Mechanisms and Advances in Clinical Trials. Molecular Cancer 2019, 18: 26.

[72] Fontana F, Giannitti G, Marchesi S, Limonta P: The PI3K/Akt Pathway and Glucose Metabolism: A Dangerous Liaison in Cancer. International Journal of Biological Sciences 2024, 20: 3113-3125.

[73] Noorolyai S, Shajari N, Baghbani E, Sadreddini S, Baradaran B: The Relation between PI3K/AKT Signalling Pathway and Cancer. Gene 2019, 698: 120-128.

[74] Huang X, You L, Nepovimova E, Psotka M, Malinak D, Valko M, et al.: Inhibitors of Phosphoinositide 3-kinase (PI3K) and Phosphoinositide 3-kinase-related Protein Kinase Family (PIKK). Journal of Enzyme Inhibition and Medicinal Chemistry 2023, 38: 2237209.

[75] Koch H, Wilhelm M, Ruprecht B, Beck S, Frejno M, Klaeger S, et al.: Phosphoproteome Profiling Reveals Molecular Mechanisms of Growth-Factor-Mediated Kinase Inhibitor Resistance in EGFR-Overexpressing Cancer Cells. Journal of Proteome Research 2016, 15: 4490-4504.

[76] Álvarez RM, García AB, Riesco-Fagundo C, Martín JI, Varela C, Rodríguez Hergueta A, et al.: Omipalisib Inspired Macrocycles as Dual PI3K/mTOR Inhibitors. European Journal of Medicinal Chemistry 2021, 211: 113109.

[77] Knight SD, Adams ND, Burgess JL, Chaudhari AM, Darcy MG, Donatelli CA, et al.: Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. ACS Medicinal Chemistry Letters 2010, 1: 39-43.

[78] To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T, et al.: Targeting Phosphoinositide-3-kinase-delta with Theophylline Reverses Corticosteroid Insensitivity in Chronic Obstructive Pulmonary Disease. American Journal of Respiratory and Critical Care Medicine 2010, 182: 897-904.

[79] Xiang Q, Dong S, Li XH: A Review of Phosphocreatine 3 Kinase δ Subtype (PI3Kδ) and Its Inhibitors in Malignancy. Medical Science Monitor 2021, 27: e932772.

[80] Wang X, Ding J, Meng LH: PI3K Isoform-selective Inhibitors: Next-generation Targeted Cancer Therapies. Acta Pharmacologica Sinica 2015, 36: 1170-1176.

[81] Spencer JA, Baldwin IR, Barton N, Chung CW, Convery MA, Edwards CD, et al.: Design and Development of a Macrocyclic Series Targeting Phosphoinositide 3-Kinase δ. ACS Medicinal Chemistry Letters 2020, 11: 1386-1391.

[82] Chen S, Yang Y, Yuan Y, Bo L: Targeting PIM Kinases in Cancer Therapy: An Update on Pharmacological Small-molecule Inhibitors. European Journal of Medicinal Chemistry 2024, 264: 116016.

[83] Alvarado Y, Giles FJ, Swords RT: The PIM Kinases in Hematological Cancers. Expert Review of Hematology 2012, 5: 81-96.

[84] Rout AK, Dehury B, Parida SN, Rout SS, Jena R, Kaushik N, et al.: A Review on Structure-function Mechanism and Signaling Pathway of Serine/Threonine Protein PIM Kinases as a Therapeutic Target. International Journal of Biological Macromolecules 2024, 270: 132030.

[85] Walhekar V, Bagul C, Kumar D, Muthal A, Achaiah G, Kulkarni R: Topical Advances in PIM Kinases and Their Inhibitors: Medicinal Chemistry Perspectives. Biochimica et biophysica acta. Reviews on Cancer 2022, 1877: 188725.

[86] Xu J, Shen C, Xie Y, Qiu B, Ren X, Zhou Y, et al.: Design, Synthesis, and Bioactivity Evaluation of Macrocyclic benzo[b]pyrido[4,3-e][1,4]oxazine Derivatives as Novel Pim-1 Kinase Inhibitors. Bioorganic & Medicinal Chemistry Letters 2022, 72: 128874.

[87] Bullock AN, Debreczeni J, Amos AL, Knapp S, Turk BE: Structure and Substrate Specificity of the Pim-1 Kinase. The Journal of Biological Chemistry 2005, 280: 41675-41682.

[88] Li G, Zhang W, Xie Y, Li Y, Cao R, Zheng G, et al.: Structure-Based Optimization of 10-DEBC Derivatives as Potent and Selective Pim-1 Kinase Inhibitors. Journal of Chemical Information and Modeling 2020, 60: 3287-3294.

[89] Regua AT, Doheny D, Arrigo A, Lo HW: Trk Receptor Tyrosine Kinases in Metastasis and Cancer Therapy. Discovery Medicine 2019, 28: 195-203.

[90] Amatu A, Sartore-Bianchi A, Bencardino K, Pizzutilo EG, Tosi F, Siena S: Tropomyosin Receptor Kinase (TRK) Biology and the Role of NTRK Gene Fusions in Cancer. Annals of Oncology 2019, 30: viii5-viii15.

[91] Drilon A: TRK Inhibitors in TRK Fusion-positive Cancers. Annals of Oncology 2019, 30: viii23-viii30.

[92] Russo M, Misale S, Wei G, Siravegna G, Crisafulli G, Lazzari L, et al.: Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer. Cancer Discovery 2016, 6: 36-44.

[93] Cocco E, Scaltriti M, Drilon A: NTRK Fusion-positive Cancers and TRK Inhibitor Therapy. Nature Reviews Clinical Oncology 2018, 15: 731-747.

[94] Xiang S, Lu X: Selective Type II TRK Inhibitors Overcome xDFG Mutation Mediated Acquired Resistance to the Second-generation Inhibitors Selitrectinib and Repotrectinib. Acta Pharmaceutica Sinica B 2024, 14: 517-532.

[95] Wang Z, Wang J, Wang Y, Xiang S, Song X, Tu Z, et al.: Discovery of the First Highly Selective and Broadly Effective Macrocycle-Based Type II TRK Inhibitors that Overcome Clinically Acquired Resistance. Journal of Medicinal Chemistry 2022, 65: 6325-6337.

[96] Wang Z, Wang J, Wang Y, Xiang S, Zhou H, Song S, et al.: Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity Against Solvent-Front, xDFG, and Gatekeeper Mutations. Journal of Medicinal Chemistry 2023, 66: 12950-12965.

[97] Berger S, Martens UM, Bochum S: Larotrectinib (LOXO-101). Recent Results in Cancer Research Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 2018, 211: 141-151.

[98] El-Nassan HB, Al-Qadhi MA: Recent Advances in the Discovery of Tropomyosin Receptor Kinases TRKs Inhibitors: A Mini Review. European Journal of Medicinal Chemistry 2023, 258: 115618.

[99] Li P, Cai S, Zhao T, Xu L, Guan D, Li J, et al.: Design, Synthesis and Biological Evaluation of Macrocyclic Derivatives as TRK Inhibitors. Bioorganic & Medicinal Chemistry Letters 2021, 53: 128409.

[100] Drilon A, Ou SI, Cho BC, Kim DW, Lee J, Lin JJ, et al.: Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent-Front Mutations. Cancer Discovery 2018, 8: 1227-1236.

[101] Florou V, Nevala-Plagemann C, Whisenant J, Maeda P, Gilcrease GW, Garrido-Laguna I: Clinical Activity of Selitrectinib in a Patient With Mammary Analogue Secretory Carcinoma of the Parotid Gland With Secondary Resistance to Entrectinib. Journal of the National Comprehensive Cancer Network 2021, 19: 478-482.

[102] Liu Z, Yu P, Dong L, Wang W, Duan S, Wang B, et al: Discovery of the Next-Generation Pan-TRK Kinase Inhibitors for the Treatment of Cancer. Journal of Medicinal Chemistry 2021, 64: 10286-10296.

[103] Harvey RD, Adams VR, Beardslee T, Medina P: Afatinib for the Treatment of EGFR Mutation-Positive NSCLC: A Review of Clinical Findings. Journal of Oncology Pharmacy Practice 2020, 26: 1461-1474.

[104] Nickel J, Sebald W, Groppe JC, Mueller TD: Intricacies of BMP Receptor Assembly. Cytokine & Growth Factor Reviews 2009, 20: 367-377.

[105] Cuthbertson I, Morrell NW, Caruso P: BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension. Circulation Research 2023, 132: 109-126.

[106] Jiramongkolchai P, Owens P, Hong CC: Emerging Roles of the Bone Morphogenetic Protein Pathway in Cancer: Potential Therapeutic Target for Kinase Inhibition. Biochemical Society Transactions 2016, 44: 1117-1134.

[107] Pousada G, Lupo V, Cástro-Sánchez S, Álvarez-Satta M, Sánchez-Monteagudo A, Baloira A, et al.: Molecular and Functional Characterization of the BMPR2 Gene in Pulmonary Arterial Hypertension. Scientific Reports 2017, 7: 1923.

[108] Amrhein JA, Wang G, Berger BT, Berger LM, Kalampaliki AD, Krämer A, et al.: Design and Synthesis of Pyrazole-Based Macrocyclic Kinase Inhibitors Targeting BMPR2. ACS Medicinal Chemistry Letters 2023, 14: 833-840.

[109] Couñago RM, Allerston CK, Savitsky P, Azevedo H, Godoi PH, Wells CI, et al.: Structural Characterization of Human Vaccinia-Related Kinases (VRK) Bound to Small-molecule Inhibitors Identifies Different P-loop Conformations. Scientific Reports 2017, 7: 7501.

[110] Mandal R, Becker S, Strebhardt K: Targeting CDK9 for Anti-Cancer Therapeutics. Cancers 2021, 13: 2181.

[111] Huang Z, Wang T, Wang C, Fan Y: CDK9 Inhibitors in Cancer Research. RSC Medicinal Chemistry 2022, 13: 688-710.

[112] Cidado J, Boiko S, Proia T, Ferguson D, Criscione SW, San Martin M, et al.: AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells. Clinical Cancer Research 2020, 26: 922-934.

[113] Zhang Y, Shan L, Tang W, Ge Y, Li C, Zhang J: Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications. Journal of Medicinal Chemistry 2024, 67: 5185-5215.

[114] Wu T, Yu B, Xu Y, Du Z, Zhang Z, Wang Y, et al.: Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer. Journal of Medicinal Chemistry 2023, 66: 15340-15361.

[115] Ganuza M, Sáiz-Ladera C, Cañamero M, Gómez G, Schneider R, Blasco MA, et al.: Genetic Inactivation of Cdk7 Leads to Cell Cycle Arrest and Induces Premature Aging Due to Adult Stem Cell Exhaustion. The EMBO Journal 2012, 31: 2498-2510.

[116] Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, et al.: Targeting Transcription Regulation in Cancer with a Covalent CDK7 Inhibitor. Nature 2014, 511: 616-620.

[117] Sava GP, Fan H, Coombes RC, Buluwela L, Ali S: CDK7 Inhibitors as Anticancer Drugs. Cancer Metastasis Reviews 2020, 39: 805-823.

[118] Niu P, Tao Y, Lin G, Xu H, Meng Q, Yang K, et al.: Design and Synthesis of Novel Macrocyclic Derivatives as Potent and Selective Cyclin-Dependent Kinase 7 Inhibitors. Journal of Medicinal Chemistry 2024, 67: 6099-6118.

[119] Constantin TA, Varela-Carver A, Greenland KK, de Almeida GS, Olden E, Penfold L, et al.: The CDK7 Inhibitor CT7001 (Samuraciclib) Targets Proliferation Pathways to Inhibit Advanced Prostate Cancer. British Journal of Cancer 2023, 128: 2326-2337.

[120] Greber BJ, Remis J, Ali S, Nogales E: 2.5 Å-resolution Structure of Human CDK-activating Kinase Bound to the Clinical Inhibitor ICEC0942. Biophysical Journal 2021, 120: 677-686.

[121] Hazel P, Kroll SH, Bondke A, Barbazanges M, Patel H, Fuchter MJ, et al.: Inhibitor Selectivity for Cyclin-Dependent Kinase 7: A Structural, Thermodynamic, and Modelling Study. ChemMedChem 2017, 12: 372-380.

[122] Niu P, Tao Y, Meng Q, Huang Y, Li S, Ding K, et al.: Discovery of Novel Macrocyclic Derivatives as Potent and Selective Cyclin-dependent Kinase 2 Inhibitors. Bioorganic & Medicinal Chemistry 2024, 104: 117711.

[123] Midha A, Dearden S, McCormack R: EGFR Mutation Incidence in Non-small-cell Lung Cancer of Adenocarcinoma Histology: A Systematic Review and Global Map by Ethnicity (mutMapII). American Journal of Cancer Research 2015, 5: 2892-2911.

[124] Sabbah DA, Hajjo R, Sweidan K: Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Current Topics in Medicinal Chemistry 2020, 20: 815-834.

[125] Uribe ML, Marrocco I, Yarden Y: EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance. Cancers 2021, 13: 2748.

[126] Park K, Tan EH, O’Byrne K, Zhang L, Boyer M, Mok T, et al.: Afatinib Versus Gefitinib as First-line Treatment of Patients with EGFR Mutation-positive Non-small-cell Lung Cancer (LUX-Lung 7): A Phase 2B, Open-label, Randomised Controlled Trial. The Lancet Oncology 2016, 17: 577-589.

[127] Wang S, Cang S, Liu D: Third-generation Inhibitors Targeting EGFR T790M Mutation in Advanced Non-small Cell Lung Cancer. Journal of Hematology & Oncology 2016, 9: 34.

[128] Das D, Xie L, Hong J: Next-generation EGFR Tyrosine Kinase Inhibitors to Overcome C797S Mutation in Non-small Cell Lung Cancer (2019-2024). RSC Medicinal Chemistry 2024, 15: 3371-3394.

[129] Engelhardt H, Böse D, Petronczki M, Scharn D, Bader G, Baum A, et al.: Start Selective and Rigidify: The Discovery Path Toward a Next Generation of EGFR Tyrosine Kinase Inhibitors. Journal of Medicinal Chemistry 2019, 62: 10272-10293.

[130] Chen H, Lai M, Zhang T, Chen Y, Tong L, Zhu S, et al.: Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations. Journal of Medicinal Chemistry 2022, 65: 6840-6858.

[131] Malapelle U, Ricciuti B, Baglivo S, Pepe F, Pisapia P, Anastasi P, et al.: Osimertinib. Recent Results in Cancer Research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 2018, 211: 257-276.

[132] Shen Y, Xiao X, Zhang P, Wang Q, Zhu X, Yang Y, et al.: Design, Synthesis and Biological Evaluation of Novel Macrocyclic Derivatives Bearing Aniline Pyrimidine Scaffolds as EGFR-TKIs. Bioorganic & Medicinal Chemistry Letters 2022, 75: 128970.

[133] Rawluk J, Waller CF: Gefitinib. Recent Results in Cancer Research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 2018, 211: 235-246.

[134] Steins M, Thomas M, Geissler M: Erlotinib. Recent Results in Cancer Research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 2010, 184: 21-31.

[135] Amrhein JA, Beyett TS, Feng WW, Krämer A, Weckesser J, Schaeffner IK, et al.: Macrocyclization of Quinazoline-Based EGFR Inhibitors Leads to Exclusive Mutant Selectivity for EGFR L858R and Del19. Journal of Medicinal Chemistry 2022, 65: 15679-15697.

[136] Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, et al.: Structures of Lung Cancer-derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity. Cancer Cell 2007, 11: 217-227.

[137] Ling P, Meyer CF, Redmond LP, Shui JW, Davis B, Rich RR, et al.: Involvement of Hematopoietic Progenitor Kinase 1 in T Cell Receptor Signaling. The Journal of Biological Chemistry 2001, 276: 18908-18914.

[138] Zhang Q, Ding S, Zhang H: Interactions Between Hematopoietic Progenitor Kinase 1 and its Adaptor Proteins (Review). Molecular Medicine Reports 2017, 16: 6472-6482.

[139] Hernandez S, Qing J, Thibodeau RH, Du X, Park S, Lee HM, et al.: The Kinase Activity of Hematopoietic Progenitor Kinase 1 is Essential for the Regulation of T Cell Function. Cell Reports 2018, 25: 80-94.

[140] Linney ID, Kaila N: Inhibitors of Immuno-oncology Target HPK1 - A Patent Review (2016 to 2020). Expert Opinion on Therapeutic Patents 2021, 31: 893-910.

[141] Zhou L, Wang T, Zhang K, Zhang X, Jiang S: The Development of Small-molecule Inhibitors Targeting HPK1. European Journal of Medicinal Chemistry 2022, 244: 114819.

[142] Chuang HC, Lan JL, Chen DY, Yang CY, Chen YM, Li JP, et al.: The Kinase GLK Controls Autoimmunity and NF-κB Signaling by Activating the Kinase PKC-θ in T cells. Nature Immunology 2011, 12: 1113-1118.

[143] Wang MS, Wang ZZ, Li ZL, Gong Y, Duan CX, Cheng QH, et al.: Discovery of Macrocycle-Based HPK1 Inhibitors for T-Cell-Based Immunotherapy. Journal of Medicinal Chemistry 2023, 66: 611-626.

[144] Lau WL, Pearce B, Malakian H, Rodrigo I, Xie D, Gao M, et al.: Using Yeast Surface Display to Engineer a Soluble and Crystallizable Construct of Hematopoietic Progenitor Kinase 1 (HPK1). Acta Crystallographica Section F Structural Biology Communications 2021, 77: 22-28.

[145] Thompson BJ, Sahai E: MST Kinases in Development and Disease. The Journal of Cell Biology 2015, 210: 871-882.

[146] Sugden PH, McGuffin LJ, Clerk A: SOcK, MiSTs, MASK and STicKs: the GCKIII (Germinal Centre Kinase III) Kinases and Their Heterologous Protein-protein Interactions. The Biochemical Journal 2013, 454: 13-30.

[147] Delpire E, Gagnon KB: SPAK and OSR1: STE20 Kinases Involved in the Regulation of Ion Homoeostasis and Volume Control in Mammalian Cells. The Biochemical Journal 2008, 409: 321-331.

[148] Schinkmann K, Blenis J: Cloning and Characterization of a Human STE20-like Protein Kinase with Unusual Cofactor Requirements. The Journal of Biological Chemistry 1997, 272: 28695-28703.

[149] Cho CY, Lee KT, Chen WC, Wang CY, Chang YS, Huang HL, et al.: MST3 Promotes Proliferation and Tumorigenicity Through the VAV2/Rac1 Signal Axis in Breast Cancer. Oncotarget 2016, 7: 14586-14604.

[150] Amrhein JA, Berger LM, Balourdas DI, Joerger AC, Menge A, Krämer A, et al.: Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3. Journal of Medicinal Chemistry 2024, 67: 674-690.

[151] Matsukawa J, Matsuzawa A, Takeda K, Ichijo H: The ASK1-MAP Kinase Cascades in Mammalian Stress Response. Journal of Biochemistry 2004, 136: 261-265.

[152] Hayakawa T, Matsuzawa A, Noguchi T, Takeda K, Ichijo H: The ASK1-MAP Kinase Pathways in Immune and Stress Responses. Microbes and Infection 2006, 8: 1098-1107.

[153] Kawarazaki Y, Ichijo H, Naguro I: Apoptosis Signal-regulating Kinase 1 as a Therapeutic Target. Expert Opinion on Therapeutic Targets 2014, 18: 651-664.

[154] Himmelbauer MK, Xin Z, Jones JH, Enyedy I, King K, Marcotte DJ, et al.: Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors. Journal of Medicinal Chemistry 2019, 62: 10740-10756.

[155] Ji N, Yang Y, Cai CY, Lei ZN, Wang JQ, Gupta P, et al.: Selonsertib (GS-4997), an ASK1 Inhibitor, Antagonizes Multidrug Resistance in ABCB1- and ABCG2-overexpressing Cancer Cells. Cancer Letters 2019, 440-441: 82-93.

[156] Shao Y, Zhang S, Zhang Y, Liu Z: Recent Advance of Spleen Tyrosine Kinase in Diseases and Drugs. International Immunopharmacology 2021, 90: 107168.

[157] Kurniawan DW, Storm G, Prakash J, Bansal R: Role of Spleen Tyrosine Kinase in Liver Diseases. World Journal of Gastroenterology 2020, 26: 1005-1019.

[158] Tsang E, Giannetti AM, Shaw D, Dinh M, Tse JK, Gandhi S, et al.: Molecular Mechanism of the Syk Activation Switch. The Journal of Biological Chemistry 2008, 283: 32650-32659.

[159] Braegelmann C, Hölzel M, Ludbrook V, Dickson M, Turan N, Ferring-Schmitt S, et al.: Spleen Tyrosine Kinase (SYK) is a Potential Target for the Treatment of Cutaneous Lupus Erythematosus Patients. Experimental Dermatology 2016, 25: 375-379.

[160] Uckun FM, Qazi S: SYK as a New Therapeutic Target in B-Cell Precursor Acute Lymphoblastic Leukemia. Journal of Cancer Therapy 2014, 5: 124-131.

[161] Grimster NP, Gingipalli L, Balazs A, Barlaam B, Boiko S, Boyd S, et al.: Optimization of a Series of Novel, Potent and Selective Macrocyclic SYK Inhibitors. Bioorganic & Medicinal Chemistry Letters 2023, 91: 129352.

[162] Grimster NP, Gingipalli L, Barlaam B, Su Q, Zheng X, Watson D, et al.: Optimization of a Series of Potent, Selective and Orally Bioavailable SYK Inhibitors. Bioorganic & Medicinal Chemistry Letters 2020, 30: 127433.

[163] Amrhein JA, Knapp S, Hanke T: Synthetic Opportunities and Challenges for Macrocyclic Kinase Inhibitors. Journal of Medicinal Chemistry 2021, 64: 7991-8009.