jm500413g_si_001.pdf (6.27 MB)
Development and Biological Evaluation of Potent and Selective c‑KITD816V Inhibitors
journal contribution
posted on 2014-08-14, 00:00 authored by Soyoung Lee, Hyunseung Lee, Jinhee Kim, Suhyun Lee, Soo Jung Kim, Byong-Seok Choi, Soon-Sun Hong, Sungwoo HongThe
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.