Rational Design and Synthesis of Novel Allosteric Hsp70 Inhibitors via a Scaffold-hopping Strategy

Abstract

Heat shock protein 70 (Hsp70) family proteins play a critical role in chronic myeloid leukemia (CML) cells’ survival. Based on the Hsp70 inhibitor JG-98, we developed a new class of inhibitors via a scaffold-hopping strategy. A “privileged structure” in medicinal chemistry replaces the benzothiazole group of JG-98. Through optimization, structure-activity relationship (SAR) analysis, and molecular docking, we gained compounds Q3 and Q4, which achieved the same level of ATPase activity inhibition of mitochondrial Hsp70, GRP75, as JG-98. They exhibit a lower molecular weight than JG-98. Q3 and Q4 maintain a comparable cytotoxic activity with JG-98 against the CML cell line, K562 cells.

Keywords

Heat shock protein 70 (Hsp70) family protein / Antitumor / Structure-activity relationship

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RIGHTS & PERMISSIONS

Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH