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A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors

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posted on 20.11.2017 by Sarah M. Bronner, Jeremy Murray, F. Anthony Romero, Kwong Wah Lai, Vickie Tsui, Patrick Cyr, Maureen H. Beresini, Gladys de leon Boenig, Zhongguo Chen, Edna F. Choo, Kevin R. Clark, Terry D. Crawford, Hariharan Jayaram, Susan Kaufman, Ruina Li, Yingjie Li, Jiangpeng Liao, Xiaorong Liang, Wenfeng Liu, Justin Ly, Jonathan Maher, John Wai, Fei Wang, Aijun Zheng, Xiaoyu Zhu, Steven Magnuson
The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we disclosed the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind the KAc region and then building into the LPF shelf. Herein, we report the “hybridization” of a variety of KAc-binding fragments with a tetrahydroquinoline scaffold that makes optimal interactions with the LPF shelf, imparting enhanced potency and selectivity to the hybridized ligand. To demonstrate the utility of our hybridization approach, two analogues containing unique Asn binders and the optimized tetrahydroquinoline moiety were rapidly optimized to yield single-digit nanomolar inhibitors of CBP with exquisite selectivity over BRD4(1) and the broader bromodomain family.

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