Structural highlights
Function[BRPF1_HUMAN] Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity. Positively regulates the transcription of RUNX1 and RUNX2.[1] [2] Publication Abstract from PubMedThe 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 (Fpo 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. Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies.,Igoe N, Bayle ED, Fedorov O, Tallant C, Savitsky P, Rogers C, Owen DR, Deb G, Somervaille TC, Andrews DM, Jones N, Cheasty A, Ryder H, Brennan PE, Muller S, Knapp S, Fish PV J Med Chem. 2017 Jan 26;60(2):668-680. doi: 10.1021/acs.jmedchem.6b01583. Epub, 2017 Jan 9. PMID:28068087[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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