KATs off: Biomedical insights from lysine acetyltransferase inhibitors

Abstract

Lysine acetyltransferase (KAT) enzymes including the p300, MYST, and GCN5 families play major roles in modulating the structure of chromatin and regulating transcription. Because of their dysregulation in various disease states including cancer, efforts to develop inhibitors of KATs have steadily gained momentum. Here we provide an overview of recent progress on the development of high quality chemical probes of the p300 and MYST family of KATs and how they are emerging as useful tools for basic and translational investigation.

Keywords: Acetyltransferase; CBP; GCN5; MYST; PCAF; p300.

Figure 1.. Small molecule KAT inhibitors.

Representative small molecule inhibitors of p300/CBP (top) and MYST (bottom) family acetyltransferases that have been linked to pharmacological studies described here. All the depicted p300/CBP inhibitors are active site competitive, except where parenthetically noted. MYST family member isoform selectivity is noted parenthetically.

Figure 2.. P300 catalytic domain substrate interactions and drug bound state.

Left. Catalytic interactions of the p300 HAT domain (white) including electrostatic interactions between Arg1410 (yellow) and the phosphodiester and phosphate of CoA, stabilizing proton donation from Tyr1467 (yellow) to the CoA thioester, and hydrogen bonding between the carbonyl of Trp1436 (yellow) and the substrate lysine Nε (PDBID 3BIY, 4PZS).^{, ,} Composite substrate-bound structure was energy minimized using Rosetta 3.13 fast relax. Right. Occupancy of the acetyl-CoA binding site by competitive ligand A-485 (pink) with hydrogen bonding interactions between the N-methyl urea and carbonyl of Gln1455 (yellow), and hydrogen bonding between Ser1400 (yellow) and one carbonyl of the spiroxazolidinedione illustrated. This binding is anchored by numerous additional hydrophobic interactions that are not depicted here (PDBID 5KJ2).

Figure 3.. KAT6 catalytic domain substrate interactions and drug bound state.

Left. Catalytic interactions of the MYST1 HAT domain (white) including hydrogen bonding between the phosphodiester and phosphate of CoA and the backbone amides of Arg655, Gly657, Gly659 and R660 (yellow). Hydrogen bonding between the carbonyl of Glu680 Pro682 (yellow) direct the substrate lysine Nε (PDBID 6BA4, 6VO5).^, Composite substrate-bound structure was energy minimized using Rosetta 3.13 fast relax. Right. Occupancy of the acetyl-CoA binding site by competitive ligand WM-8014 (pink) including hydrogen bonding interactions between the acylsulfonylhydrazide core and the backbone amides of Arg655, Gly657, Gly659 and R660 (yellow). This binding is anchored by additional hydrophobic interactions that are not depicted here (PDBID 6CT2).