Targeting Gain of Function and Resistance Mutations in Abl and KIT by Hybrid Compound Design

详细信息    查看全文

• 作者：Andr茅 Richters ; Julia Ketzer ; Matth盲us Getlik ; Christian Gr眉tter ; Ralf Schneider ; Johannes M. Heuckmann ; Stefanie Heynck ; Martin L. Sos ; Anu Gupta ; Anke Unger ; Carsten Schultz-Fademrecht ; Roman K. Thomas ; Sebastian Bauer ; Daniel Rauh
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 25, 2013
• 年：2013
• 卷：56
• 期：14
• 页码：5757-5772
• 全文大小：689K
• 年卷期：v.56,no.14(July 25, 2013)
• ISSN：1520-4804

文摘

Mutations in the catalytic domain at the gatekeeper position represent the most prominent drug-resistant variants of kinases and significantly impair the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular and atomic levels will aid in the design and development of inhibitors that have the potential to overcome these resistance mutations. Herein, by introducing adaptive elements into the inhibitor core structure, we undertake the structure-based development of type II hybrid inhibitors to overcome gatekeeper drug-resistant mutations in cSrc-T338M, as well as clinically relevant tyrosine kinase KIT-T670I and Abl-T315I variants, as essential targets in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). Using protein X-ray crystallography, we confirm the anticipated binding mode in cSrc, which proved to be essential for overcoming the respective resistances. More importantly, the novel compounds effectively inhibit clinically relevant gatekeeper mutants of KIT and Abl in biochemical and cellular studies.