PDBsum entry 4cfk

Cell cycle

PDB id: 4cfk

Contents

Protein chain

127 a.a.

Ligands

GOL

LY2

EDO

Waters ×238

References listed in PDB file

Key reference

• Title: The commonly used pi3-Kinase probe ly294002 is an inhibitor of bet bromodomains.
• Authors: A.Dittmann, T.Werner, C.W.Chung, M.M.Savitski, M.Fälth savitski, P.Grandi, C.Hopf, M.Lindon, G.Neubauer, R.K.Prinjha, M.Bantscheff, G.Drewes.
• Ref.: Acs Chem Biol, 2014, 9, 495-502. [DOI no: 10.1021/cb400789e]
• PubMed id: 24533473

Abstract

A commonly used small-molecule probe in cell-signaling research is the phosphoinositide 3-kinase inhibitor LY294002. Quantitative chemoproteomic profiling shows that LY294002 and LY303511, a close analogue devoid of PI3K activity, inhibit the BET bromodomain proteins BRD2, BRD3, and BRD4 that comprise a family of targets structurally unrelated to PI3K. Both compounds competitively inhibit acetyl-lysine binding of the first but not the second bromodomain of BET proteins in cell extracts. X-ray crystallography shows that the chromen-4-one scaffold represents a new bromodomain pharmacophore and establishes LY294002 as a dual kinase and BET-bromodomain inhibitor, whereas LY303511 exhibits anti-inflammatory and antiproliferative effects similar to the recently discovered BET inhibitors.