6AY3

CREBBP bromodomain in complex with Cpd16 (5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1H-indole-3-carboxamide)

Summary for 6AY3

• Entry DOI: 10.2210/pdb6ay3/pdb
• Related: 6AXQ 6AY5
• Descriptor: CREB-binding protein, 5-[7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl]-N-methyl-1H-indole-3-carboxamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: crebbp, bromodomain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q92793
• Total number of polymer chains: 2
• Total formula weight: 28455.47

Authors

Murray, J.M. (deposition date: 2017-09-07, release date: 2018-02-21, Last modification date: 2023-10-04)

Primary citation

Bronner, S.M.,Murray, J.,Romero, F.A.,Lai, K.W.,Tsui, V.,Cyr, P.,Beresini, M.H.,de Leon Boenig, G.,Chen, Z.,Choo, E.F.,Clark, K.R.,Crawford, T.D.,Jayaram, H.,Kaufman, S.,Li, R.,Li, Y.,Liao, J.,Liang, X.,Liu, W.,Ly, J.,Maher, J.,Wai, J.,Wang, F.,Zheng, A.,Zhu, X.,Magnuson, S.
A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors.
J. Med. Chem., 60:10151-10171, 2017

PubMed Abstract: 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.

PubMed: 29155580
DOI: 10.1021/acs.jmedchem.7b01372

Experimental method

X-RAY DIFFRACTION (1.391 Å)