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