We have recently identified BPR1K432 (1), 1 a potent Aurora kinase A inhibitor (IC 50 ~50 nM), which possessed anti-proliferative activity in HCT-116 cell line (IC 50 ~400 nM). However, it was inactive in HCT-116 tumor xenograft nude mouse model. Hence we initiated optimization of the lead 1. Structure-activity relationship studies in the urea side chain (Strategy II) and modification in the phenyl rings (Strategy I) were carried out, resulting in the identification of BPR1K724, with improved drug like property and better in vitro anti-proliferative activity than the lead 1. Most importantly, the optimized lead BPR1K724 showed potent in vivo anti-tumor efficacy in HCT-116 tumor xenograft nude mouse model. The detailed SAR study leading to the identification of optimized lead BPR1K724 will be disclosed.
Date:
2010-08
Relation:
Abstracts of Papers - American Chemical Society. 2010 Aug;240:MEDI 332.
