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

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Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
Wuxi Apptec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People’s Republic of China
§ Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States
*For F.A.R. phone, (858) 349-6055; E-mail, [email protected]
*For S.M. E-mail, [email protected]
Cite this: J. Med. Chem. 2017, 60, 22, 9162–9183
Publication Date (Web):September 11, 2017
Copyright © 2017 American Chemical Society
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Abstract Image

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.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00796.

  • Full experimental details and characterization for all reported compounds, BromoScan data for 10 and 19, Cerep off-target screening data for 19, Invitrogen kinase data for 19, ab initio torsion scan data for 8, PK/PD data for 19, crystallography methods for 3-CBP, 8-CBP, 17-CBP, 10-CBP, 19-CBP, and 19-BRD4(1) (PDF)

  • Molecular formula strings (CSV)

Accession Codes

PDB codes for the structures of the CBP bromodomain in complex with 3, 8, 17, 10, and 19 are 5W0F, 5W0I, 5W0L, 5W0Q, and 5W0E, respectively. PDB code for the structure of the BRD4(1) in complex with 19 is 5VZS. Authors will release the atomic coordinates and experimental data upon article publication.

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