First dual aromatase-steroid sulfatase inhibitors.
Aromatase inhibitors in clinical use block the biosynthesis of estrogens. Hydrolysis of estrone 3-sulfate by steroid sulfatase is an important additional source of tumor estrogen, and blockade of both enzymes should provide a more effective endocrine therapy. Sulfamoylated derivatives of the aromatase inhibitor YM511 inhibited sulfatase and aromatase in JEG-3 cells with respective IC(50) values of 20-227 and 0.82-100 nM (cf. letrozole, 0.89 nM). One dual inhibitor was potent against both enzymes in vivo, validating the concept.
Woo
L W Lawrence
LW
Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Claverton Down, Bath BA2 7AY, UK.
Sutcliffe
Oliver B
OB
Bubert
Christian
C
Grasso
Anna
A
Chander
Surinder K
SK
Purohit
Atul
A
Reed
Michael J
MJ
Potter
Barry V L
BV
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047072:Aromatase Inhibitors; D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004958:Estradiol / Q000032:analysis / Q000097:blood; D004965:Estrogen Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D008099:Liver / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D043266:Steryl-Sulfatase
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D004958:Estradiol; D001192:Arylsulfatases; D043266:Steryl-Sulfatase