1615223-35-2

Upstream product

• 122775-35-3 3,4-Dimethoxyphenylboronic acid 
• 757978-19-1 5-bromo-3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine 
• 1261082-88-5 5-bromo-3-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine 
• 73183-34-3 bis(pinacol)diborane 

Downstream Products

• 1615223-18-1 (3-amino-5-(3-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone 
• 1615223-19-2 5-(3-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-morpholinoethoxy)aniline 

Relevant academic research and scientific papers

Structure-based de novo design and identification of D816V mutant-selective c-KIT inhibitors

To identify potent and selective inhibitors of D816V, the most common gain-of-function c-KIT mutant, we carried out structure-based de novo design using 7-azaindole as the core and the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of new c-KIT inhibitors specific for the D816V mutant. The 3-(3,4- dimethoxyphenyl)-7-azaindole scaffold was optimized and represents a lead structure for the design of the potent and specific inhibitors of the D816V mutant. The results of molecular dynamics simulations indicate that hydrogen bonding interactions between the 7-azadindole moiety and the backbone groups of Cys673 are the most significant determinant for the potency and selectivity of c-KIT inhibitors. This journal is

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.