Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies

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.

Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains

“…Interestingly, a newly described quinoline-2-one inhibitor targeting mainly BRPF1 and BRPF2 BDs also shows low micromolar activity in leukemia cell lines. 48 …”

Smart Design of Small‐Molecule Libraries: When Organic Synthesis Meets Cheminformatics

“…Such as et provedt oh ave higher shape diversity than that of other commercially available fragment libraries, as shown by the PMI plot (Figure 8), because the 52 NP-like fragments (black diamonds) significantly shifted towardsthe sphere corner. The biological relevance of this set of fragments was preliminarily demonstrated, thankst oahigh-throughput X-ray crystallographya ssay against three epigenetic targets, namely,t he ATAD2 [49] and BRD1 [50] bromodomains, and the histone demethylase JMJD2D. [51] Twoh its were found to interactw ith the JMJD2D protein, both of which targeted ap eripheral binding site, not previously detected in similar experiments,w hich could open up aw ay to new allosteric modulation of this histone demethylase enzyme.…”

Synthesis and Demonstration of the Biological Relevance of sp3‐rich Scaffolds Distantly Related to Natural Product Frameworks

“…Here, the objective was to perform a preliminary assessment of biological relevance rather than to provide specific starting points for discovery. High expression levels of ATAD2 and JMJD2 family members correlate with poor outcomes in several cancers, whilst BRD1 is a member of the BRPF family of scaffolding proteins whose role in acute myeloid leukemia is now emerging . The two bromodomains are contrasting targets: ATAD2 has a shallow N ‐acetyl lysine binding site and has been suggested to have particularly low druggability…”