Abstract 2318: BET bromodomain inhibitors for cancer therapy
Authors: Qi Jun , Filippakopoulos Panagis , McKeown Michael , Shaw Katharin L. , Smith William B. , French Christopher A. , Kung Andrew L. , Knapp Stefan , Bradner James E. 
Published: June 2012

Lysine acetylation has emerged as a signaling modification of broad relevance to cellular and disease biology. Targeting the enzymes which reversibly mediate side-chain acetylation has been an active area of drug discovery research for many years. To date, successful efforts have been limited to the “writers” (acetyltransferases) and “erasers” (histone deacetylases) of covalent modifications arising in the context of nuclear chromatin. Potent inhibitors of acetyl-lysine recognition modules, the epigenetic “readers”, have not yet been explored. Bromodomain containing proteins are structurally diverse and possessing one or more evolutionarily conserved effector modules, which can recognize acetylated lysines of histones. Recent research has established a compelling rationale for targeting BRD4 in cancer. Most importantly, BRD4 has recently been identified as a component of a recurrent t(15;19) chromosomal translocation in an aggressive form of human squamous carcinoma. Such translocations genetically define the so-called NUT midline carcinoma (NMC) by expressing the tandem N-terminal bromodomains of BRD4 as an in-frame chimera with the NUT (nuclear protein in testis) protein. Functional studies in patient-derived NMC cell lines have validated the essential role of the BRD4-NUT oncoprotein in maintaining the characteristic proliferation advantage and differentiation block of this uniformly fatal malignancy. Therefore, we have developed a cell-permeable, potent small-molecule inhibitor (JQ1) with high biochemical selectivity for the BET sub-family of bromodomain proteins. Competitive binding of JQ1 to the BRD4 fusion oncoprotein results in immediate squamous differentiation and specific anti-proliferative effects in patient-derived cell lines and in a murine xenograft model of BRD4-dependent carcinoma. These data establish the feasibility of targeting protein-protein interactions of epigenetic “readers” and reports a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family. Based on this compelling discovery, the derivatives of JQ1, a family of thieno-triazolo-1,4-diazepines, possessing variety functional groups around the core structure were synthesized to establish the structure activity relationship (SAR). We have then developed selective inhibitors to target other BET sub-family members, such as BRD2, BRD3, and BRDT. By utilizing chemical biology tools, including the library synthesis, biological assay development, and virtual screening based on the established binding module, the lead compounds have been studied using in vitro and in vivo models of several genetically-leveraged BET dependent cancers among solid tumors and hematologic malignancies. Overall, the discovery of novel bromodomain inhibitors establishes a chemical biology platform to target additional epigenetic readers of broad relevance to cancer and cellular biology.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2318. doi:10.1158/1538-7445.AM2011-2318