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.