Abstract 2528: Optimization of small molecules targeting BMI1 protein expression. Part 2. Improved potency, oral bioavailability, and in vivo efficacy of amino-pyrazines and amino-pyridines

Earlier, in our efforts to identify molecules that selectively deplete tumor stem cells, we discovered and elaborated on a series of amino-thiazoles. These first-in-class small molecule inhibitors reduce the activity and levels of BMI1 protein in vitro and in vivo (see the preceding poster). Through our medicinal chemistry efforts, we developed a second generation of molecules that reduce levels of BMI1. In this new scaffold, the central thiazole ring has been replaced with a pyrazine or pyridine ring. There is a clear relationship between the structure of the central heterocycle and the ability of the compound to decrease the level of BMI1 protein. The most beneficial modification on the right wing of the molecule is the introduction of benzimidazole moiety. As a result, analogs with markedly improved oral bioavailability have been identified. The structure activity relationship on the left ring parallels the SAR observed with the amino-thiazole scaffold. The most successful analogs in this series can be dosed orally and demonstrate dose-dependent efficacy in mouse xenograft models including the HT1080 and L1210 cell lines. Citation Format: Ramil Baiazitov, Nadiya Sydorenko, Hongyu Ren, Wu Du, Steve Paget, Richard Wilde, Ronggang Liu, Chang-Sun Lee, Liangxian Cao, Thomas W. Davis, Neil G. Almstead, Young-Choon Moon. Optimization of small molecules targeting BMI1 protein expression. Part 2. Improved potency, oral bioavailability, and in vivo efficacy of amino-pyrazines and amino-pyridines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2528. doi:10.1158/1538-7445.AM2014-2528