Structure-based design, synthesis and in vitro characterization of potent 17beta-hydroxysteroid dehydrogenase type 1 inhibitors based on 2-substitutions of estrone and D-homo-estrone.
In search for specific drugs against steroid-dependent cancers we have developed a novel set of potent inhibitors of steroidogenic human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1). The X-ray structure of 17beta-HSD 1 in complex with estradiol served as basis for the design of the inhibitors. 2-Substituted estrone and D-homo-estrone derivatives were synthesized and tested for 17beta-HSD 1 inhibition. The best 17beta-HSD 1 inhibitor, 2-phenethyl-D-homo-estrone, revealed an IC(50) of 15 nM in vitro. The inhibitory potency of compounds is comparable or better to that of previously described inhibitors. An interaction within the cofactor binding site is not necessary to obtain this high binding affinity for substances developed.
Möller
Gabriele
G
Helmholtz Zentrum München, Institute of Experimental Genetics, Genome Analysis Center, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
Deluca
Dominga
D
Gege
Christian
C
Rosinus
Andrea
A
Kowalik
Dorota
D
Peters
Olaf
O
Droescher
Peter
P
Elger
Walter
W
Adamski
Jerzy
J
Hillisch
Alexander
A
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D004970:Estrone; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase