Abstract 5427: Small molecule inhibitors of Musashi family of RNA-binding proteins

Abstract

Abstract Musashi family of RNA-binding proteins are key regulators of several stem cell populations and are also involved in tumor proliferation and maintenance. There are two Musashi proteins in humans, Msi1 and Msi2, both of which regulate target mRNAs translation. We aim to identify small molecule inhibitors of Msi activity thus blocking the growth of a broad range of cancer cells. Known mRNA targets of Msi1 include Numb, APC and p21WAF-1, key regulators of Notch, Wnt signaling and cell cycle progression, respectively. Numb is also an mRNA target of Msi2. We confirmed the binding between numb and Msi1/Msi2 by RNA-IP. Using a fluorescence polarization assay, we screened small molecules from several chemical libraries for those that disrupt the binding of Msi1 to its consensus RNA binding site. Hits were validated by surface plasmon resonance, amplified luminescent proximity homogeneous assays and nuclear magnetic resonance. Among the small molecules that we screened, we found several hit compounds that disrupt the Msi1-numb RNA binding potently. Our study supports the hypothesis that Msi1 inhibition is a viable and effective anti-cancer strategy and we identified (-)-gossypol as the first small molecule inhibitor of Msi1 that inhibits tumor xenograft growth in vivo. Citation Format: Lan Lan, Carl Appelman, Amber Smith, Jia Yu, Sarah Larsen, Rebecca Marquez, Xiaoqing Wu, Hao Liu, Anuradha Roy, Asokan Anbanandam, Ragul Gowthaman, John Karanicolas, Steven Rogers, Jeffrey Aubé, Roberto De Guzman, Kristi Neufeld, Liang Xu. Small molecule inhibitors of Musashi family of RNA-binding proteins. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5427. doi:10.1158/1538-7445.AM2015-5427