5W0L

CREBBP Bromodomain in complex with Cpd10 (1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one)

Summary for 5W0L

• Entry DOI: 10.2210/pdb5w0l/pdb
• Related: 5W0I
• Descriptor: CREB-binding protein, 1-{3-[7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl]-1-(oxan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl}ethan-1-one (3 entities in total)
• Functional Keywords: crebbp, bromodomain, small molecule inhibitor, transcription regulator-inhibitor complex, transcription regulator/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q92793
• Total number of polymer chains: 2
• Total formula weight: 36281.10

Authors

Murray, J.M. (deposition date: 2017-05-31, release date: 2018-03-07, Last modification date: 2023-10-04)

Primary citation

Romero, F.A.,Murray, J.,Lai, K.W.,Tsui, V.,Albrecht, B.K.,An, L.,Beresini, M.H.,de Leon Boenig, G.,Bronner, S.M.,Chan, E.W.,Chen, K.X.,Chen, Z.,Choo, E.F.,Clagg, K.,Clark, K.,Crawford, T.D.,Cyr, P.,de Almeida Nagata, D.,Gascoigne, K.E.,Grogan, J.L.,Hatzivassiliou, G.,Huang, W.,Hunsaker, T.L.,Kaufman, S.,Koenig, S.G.,Li, R.,Li, Y.,Liang, X.,Liao, J.,Liu, W.,Ly, J.,Maher, J.,Masui, C.,Merchant, M.,Ran, Y.,Taylor, A.M.,Wai, J.,Wang, F.,Wei, X.,Yu, D.,Zhu, B.Y.,Zhu, X.,Magnuson, S.
GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP).
J. Med. Chem., 60:9162-9183, 2017

PubMed Abstract: 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 = 0.94 nM, BRET IC = 6.2 nM; BRD4(1) IC = 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.

PubMed: 28892380
DOI: 10.1021/acs.jmedchem.7b00796

Experimental method

X-RAY DIFFRACTION (1.549 Å)