Development of inhibitors to overcome drug resistance in $c-KIT^{D816V}$ mutant and site selective C-H functionalization of isoquinolones

Abstract

Part 1. Development and Biological Evaluation of Potent and Selective c-KIT D816V Inhibitors The c-KIT tyrosine kinase has emerged as a potential therapeutic target for an array of diseases. however, there exists a drug resistance that is caused by mutations in c-KIT

therefore, c-KIT remains as a clinical challenge due to limited effective treatment options for therapies. For example, the acquired activating point mutation D816V significantly impairs the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular level will aid in designing and developing particular inhibitors with the potential to overcome these resistance mutations. We undertake a structure-based de novo design of 7-azaindole as the molecular core using the modified scoring function. This approach led to an identification of new c-KIT inhibitors over 100-fold specific for the D816V mutant relative to the wild-type c-KIT with nanomolar inhibitory activity. More importantly, these compounds potently inhibit clinically relevant D816V mutations of c-KIT in biochemical and cellular studies.

Part 2. Catalyst Controlled Divergent C-4 / C-8 Site Selective Direct Arylation of Isoquinolone The catalyst controlled C4/C8 site-selective C-H arylation of isoquinolones using aryliodonium salts as the coupling partners was developed without recourse to extra directing groups. The C4-selective arylation was successfully achieved via an electrophilic palladation pathway. The use of an Ir(III) catalytic system enables catalytic cross-coupling at the C8 position. The reaction scope is broad, and the isoquinolone scaffold can be conveniently equipped with various aryl substituents at either the C4 or C8 position.