5T4U

Crystal structure of the bromodomain of human BRPF1 in complex with a quinolinone ligand

Summary for 5T4U

• Entry DOI: 10.2210/pdb5t4u/pdb
• Descriptor: Peregrin, NITRATE ION, 1-METHYLQUINOLIN-2(1H)-ONE, ... (4 entities in total)
• Functional Keywords: transcription, structural genomics, psi-2, protein structure initiative, structural genomics consortium, sgc
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P55201
• Total number of polymer chains: 1
• Total formula weight: 13924.89

Authors

Tallant, C.,Igoe, N.,Bayle, E.D.,Nunez-Alonso, G.,Newman, J.A.,Mathea, S.,Savitsky, P.,Fedorov, O.,Brennan, P.E.,Muller, S.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Fish, P.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2016-08-30, release date: 2017-02-08, Last modification date: 2024-01-17)

Primary citation

Igoe, N.,Bayle, E.D.,Fedorov, O.,Tallant, C.,Savitsky, P.,Rogers, C.,Owen, D.R.,Deb, G.,Somervaille, T.C.,Andrews, D.M.,Jones, N.,Cheasty, A.,Ryder, H.,Brennan, P.E.,Muller, S.,Knapp, S.,Fish, P.V.
Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies.
J. Med. Chem., 60:668-680, 2017

PubMed Abstract: The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (F 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.

PubMed: 28068087
DOI: 10.1021/acs.jmedchem.6b01583

Experimental method

X-RAY DIFFRACTION (1.5 Å)