Histone-code reading by BPTF guides a peptide–small-molecule bivalent inhibitor
- The BPTF PHD–bromodomain cassette reads H3K4me3 together with K14 acetylation, a pairing confirmed by crystallography and shown to work cooperatively, including in cis.
- The authors report first experimental evidence of a ligand-induced conformational change between the two reader domains.
- A peptide–small-molecule conjugate, MJ-1, was built from these insights and inhibits both domains, addressing the usual ligandability problem of PHD fingers.
💡 Points
Everyone has chased BPTF bromodomain binders with limited payoff; the PHD finger is the hard half, and a bivalent design is a pragmatic way to borrow affinity from a peptide. The catch is that a peptide conjugate is far from a cell-permeable lead. I'd want to see which half carries the potency and whether a fully small-molecule version holds up.