10.1021/jm500413g.s001
Soyoung Lee
Soyoung
Lee
Hyunseung Lee
Hyunseung
Lee
Jinhee Kim
Jinhee
Kim
Suhyun Lee
Suhyun
Lee
Soo Jung Kim
Soo Jung
Kim
Byong-Seok Choi
Byong-Seok
Choi
Soon-Sun Hong
Soon-Sun
Hong
Sungwoo Hong
Sungwoo
Hong
Development and Biological
Evaluation of Potent and
Selective c‑KIT<sup>D816V</sup> Inhibitors
American Chemical Society
2014
D 816V mutations
therapy
inhibitor
drug resistance
point mutation D 816V
2014-08-14 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Development_and_Biological_Evaluation_of_Potent_and_Selective_c_KIT_sup_D816V_sup_Inhibitors/2264578
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.