Selective small molecule inhibitors of the potential breast cancer marker, human arylamine N-acetyltransferase 1, and its murine homologue, mouse arylamine N-acetyltransferase 2.
The identification, synthesis and evaluation of a series of rhodanine and thiazolidin-2,4-dione derivatives as selective inhibitors of human arylamine N-acetyltransferase 1 and mouse arylamine N-acetyltransferase 2 is described. The most potent inhibitors identified have submicromolar activity and inhibit both the recombinant proteins and human NAT1 in ZR-75 cell lysates in a competitive manner. (1)H NMR studies on purified mouse Nat2 demonstrate that the inhibitors bind within the putative active site of the enzyme.
Russell
Angela J
AJ
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Westwood
Isaac M
IM
Crawford
Matthew H J
MH
Robinson
James
J
Kawamura
Akane
A
Redfield
Christina
C
Laurieri
Nicola
N
Lowe
Edward D
ED
Davies
Stephen G
SG
Sim
Edith
E
D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051379:Mice; D012236:Rhodanine / Q000138:chemical synthesis* / Q000494:pharmacology; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000494:pharmacology
D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D045162:Thiazolidinediones; C500090:thiazolidine-2,4-dione; D012236:Rhodanine; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C524206:Nat2 enzyme, mouse