Synthesis of isothiazol-3-one derivatives as inhibitors of histone acetyltransferases (HATs).
High-throughput screening led to the identification of isothiazolones 1 and 2 as inhibitors of histone acetyltransferase (HAT) with IC50s of 3 microM and 5 microM, respectively. Analogues of these hit compounds with variations of the N-phenyl group, and with variety of substituents at C-4, C-5 of the thiazolone ring, were prepared and assayed for inhibition of the HAT enzyme PCAF. Potency is modestly favoured when the N-aryl group is electron deficient (4-pyridyl derivative 10 has IC(50)=1.5 microM); alkyl substitution at C-4 has little effect, whilst similar substitution at C-5 causes a significant drop in potency. The ring-fused compound 38 has activity (IC(50)=6.1 microM) to encourage further exploration of this bicyclic structure. The foregoing SAR is consistent with an inhibitory mechanism involving cleavage of the S-N bond of the isothiazolone ring by a catalytically important thiol residue.
Gorsuch
Stephen
S
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Cancer Research UK Laboratories, Cotswold Road, Sutton, Surrey, SM2 5NG, UK.
Bavetsias
Vassilios
V
Rowlands
Martin G
MG
Aherne
G Wynne
GW
Workman
Paul
P
Jarman
Michael
M
McDonald
Edward
E
D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors; D000099224:p300-CBP-Associated Factor
D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; D013844:Thiazoles; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor