GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)

作者：F. Anthony Romero, Jeremy Murray, Kwong Wah Lai, Vickie Tsui, Brian K. Albrecht, Le An, Maureen H. Beresini, Gladys de Leon Boenig, Sarah M. Bronner, Emily Chan, Kevin X. Chen, Zhongguo Chen, Edna F. Choo, Kyle Clagg, Kevin Clark, Terry D. Crawford, Patrick Cyr, Denise de Almeida Nagata, Karen E. Gascoigne, Jane L. Grogan, Georgia Hatzivassiliou, Wei Huang, Thomas Hunsaker, Susan Kaufman, Stefan G. Koenig, Ruina Li, Yingjie Li, Xiaorong Liang, Jiangpeng Liao, Wenfeng Liu, Justin Q. Ly, Jonathan Maher, Colin Masui, Mark Merchant, Yingqing Ran, Alexander M. Taylor, John Wai, Fei Wang, Xiaocang Wei, Dong Yu, Bing‐Yan Zhu, Xiaoyu Zhu, Steven Magnuson · 发表于：Journal of Medicinal Chemistry · 年份：2017 · DOI：10.1021/acs.jmedchem.7b00796 · 被引用次数：135 · 研究领域：Protein Degradation and Inhibitors、Multiple Myeloma Research and Treatments、Advanced biosensing and bioanalysis techniques

Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure–activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC 50 = 0.94 nM, BRET IC 50 = 6.2 nM; BRD4(1) IC 50 = 5100 nΜ) that maintained good in vivo PK properties in multiple species. Compound 19 displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner.