Development and Biological Evaluation of Potent and Selective c-KITD816V Inhibitors

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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.
Publisher
AMER CHEMICAL SOC
Issue Date
2014-08
Language
English
Article Type
Article
Keywords

GASTROINTESTINAL STROMAL TUMORS; TYROSINE KINASE INHIBITOR; C-KIT; ACTIVATING MUTATION; CATALYTIC DOMAIN; WILD-TYPE; MASTOCYTOSIS; IMATINIB; MECHANISMS; RESISTANT

Citation

JOURNAL OF MEDICINAL CHEMISTRY, v.57, no.15, pp.6428 - 6443

ISSN
0022-2623
DOI
10.1021/jm500413g
URI
http://hdl.handle.net/10203/201162
Appears in Collection
CH-Journal Papers(저널논문)
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