Abstract 2529: Optimization of small molecules targeting BMI1 protein expression. Part 1. Amino-thiazoles: the first-in-class highly potent inhibitors of BMI1 protein

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA BMI1 (B-cell specific Moloney Murine Leukemia Virus Insertion 1) is a gene predominantly expressed in stem cells. A deficiency of BMI1 protein leads to a reduction in the adult stem cell population. Decreasing of BMI1 protein levels by siRNA causes apoptosis and/or senescence in tumor cells in vitro and increases susceptibility to cytotoxic agents. In tumors, the level of BMI1 protein is often elevated. Consequently, the expression level of BMI1 is highly prognostic in many types of cancers. Since BMI1 is non-enzymatic, targeting this protein by traditional drug discovery approaches has not met with success. PTC Therapeutics has developed a novel screening technology referred to as GEMSTM (Gene Expression Modulation by Small molecules) to identify small molecules that modulate the levels of a protein of interest by targeting post-transcriptional regulatory processes. Using this screening technology, we have identified a number of compounds that can selectively reduce levels of BMI1 protein. Schematically, the lead scaffold could be represented by four key components: a bicyclic right core, a heterocyclic middle ring (thiazole), a linking group and a left aryl region. Structure-activity relationships associated with this series have been investigated through medicinal chemistry efforts. Incorporation of a small electron-donating para- substituent at the left part of the molecule is highly effective in decreasing levels of BMI1, indicating the strong influence of both steric and electronic effects on activity. An amino (linking group) moiety was found to be essential for activity. Variation at the right-hand moiety appears to be more tolerated, allowing improvements in both pharmacokinetic and activity profiles. These SAR findings have revealed important pharmacophoric and structural features required for the desired biological activity with this series, and provide a foundation for further lead optimization efforts. Citation Format: Nadiya Sydorenko, Ramil Baiazitov, Soongyu Choi, Chang-Sun Lee, Liangxian Cao, Thomas W. Davis, Neil G. Almstead, Young-Choon Moon. Optimization of small molecules targeting BMI1 protein expression. Part 1. Amino-thiazoles: the first-in-class highly potent inhibitors of BMI1 protein. [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 2529. doi:10.1158/1538-7445.AM2014-2529