3 years ago

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

GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)
Justin Ly, Alexander M. Taylor, Patrick Cyr, Maureen H. Beresini, Brian K. Albrecht, Wenfeng Liu, John Wai, Xiaoyu Zhu, Kevin X. Chen, Ruina Li, Denise de Almeida Nagata, Vickie Tsui, Zhongguo Chen, Emily W. Chan, F. Anthony Romero, Yingjie Li, Gladys de Leon Boenig, Bing-Yan Zhu, Fei Wang, Georgia Hatzivassiliou, Karen E. Gascoigne, Kevin Clark, Kwong Wah Lai, Susan Kaufman, Xiaocang Wei, Jonathan Maher, Edna F. Choo, Wei Huang, Xiaorong Liang, Sarah M. Bronner, Kyle Clagg, Colin Masui, Jeremy Murray, Dong Yu, Jiangpeng Liao, Stefan G. Koenig, Mark Merchant, Terry D. Crawford, Le An, Thomas L. Hunsaker, Yingqing Ran, Steven Magnuson, Jane L. Grogan
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 IC50 = 0.94 nM, BRET IC50 = 6.2 nM; BRD4(1) IC50 = 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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00796

DOI: 10.1021/acs.jmedchem.7b00796

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