TY - DATA T1 - A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors PY - 2017/11/20 AU - Sarah M. Bronner AU - Jeremy Murray AU - F. Anthony Romero AU - Kwong Wah Lai AU - Vickie Tsui AU - Patrick Cyr AU - Maureen H. Beresini AU - Gladys de leon Boenig AU - Zhongguo Chen AU - Edna F. Choo AU - Kevin R. Clark AU - Terry D. Crawford AU - Hariharan Jayaram AU - Susan Kaufman AU - Ruina Li AU - Yingjie Li AU - Jiangpeng Liao AU - Xiaorong Liang AU - Wenfeng Liu AU - Justin Ly AU - Jonathan Maher AU - John Wai AU - Fei Wang AU - Aijun Zheng AU - Xiaoyu Zhu AU - Steven Magnuson UR - https://acs.figshare.com/articles/dataset/A_Unique_Approach_to_Design_Potent_and_Selective_Cyclic_Adenosine_Monophosphate_Response_Element_Binding_Protein_Binding_Protein_CBP_Inhibitors/5688433 DO - 10.1021/acs.jmedchem.7b01372.s002 L4 - https://ndownloader.figshare.com/files/9958837 KW - selectivity KW - CBP bromodomain inhibitors KW - LPF shelf KW - hybridization KW - BRD KW - Selective Cyclic Adenosine Monophosphate Response Element Binding Protein KW - optimized tetrahydroquinoline moiety N2 - 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. ER -