Abstract SY02-03: Bromodomain inhibition in cancer

Abstract

Abstract Cellular states are maintained by coordinated gene expression programs, attributable to master regulatory transcription factors. Toward the pharmacologic control of cellular states we have undertaken a chemical biological approach to inhibit chromatin-dependent transcriptional signaling. Transcriptional activation by master regulatory proteins is facilitated by chromatin remodeling at promoter/enhancer regions, in particular side-chain acetylation of lysine residues on nearby histone tails. Context-specific lysine acetylation prompts molecular recognition by transcriptional co-activator proteins possessing acetyl-lysine recognition modules, or bromodomains. Perhaps owing to perceptions regarding the feasibility of abrogating protein-protein interactions, research toward the direct inhibition of human bromodomains (or epigenetic reader proteins, in general) has received comparatively little attention. Based on the above rationale, we have developed chemical and biochemical platforms for the development and characterization of novel bromodomain inhibitors. Recently, we reported the first potent, small-molecule inhibitor of human bromodomains, JQ1, which exhibits selectivity for the BET family of bromodomain-containing transcriptional co-activators. Of broad relevance to cancer, we will present research demonstrating that c-Myc expression is critically dependent on BRD4 function and localization to discrete upstream regulatory regions. Exposure of cancer cells to JQ1 prompts immediate down-regulation of c-Myc expression leading to suppression of a transcriptional program associated with proliferation, survival and metabolic adaptation. In translational models of Myc-dependent hematologic malignancies, the efficacy of JQ1 treatment establishes a mechanistic rationale for the leveraged clinical development of drug-like JQ1 derivatives. Toward this objective, we have completed chemical optimization of novel, drug-like inhibitors of BET bromodomains as reagents capable of supporting human clinical investigation. This research has established the feasibility of inhibiting epigenetic reader proteins with efficient, cell-permeable, small molecules. In support of an open-innovation model of chemical biology, we have created a chemical probe allowing the broad study of chromatin biology, which has already been provided to more than 150 academic, governmental and industrial laboratories worldwide. Together, we have rapidly identified mechanism-based opportunities for clinical translation in cancer, inflammation and metabolic diseases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY02-03. doi:1538-7445.AM2012-SY02-03