title: Species used for drug testing reveal different inhibition susceptibility for 17beta-hydroxysteroid dehydrogenase type 1.
abstract: Steroid-related cancers can be treated by inhibitors of steroid metabolism. In searching for new inhibitors of human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1) for the treatment of breast cancer or endometriosis, novel substances based on 15-substituted estrone were validated. We checked the specificity for different 17beta-HSD types and species. Compounds were tested for specificity in vitro not only towards recombinant human 17beta-HSD types 1, 2, 4, 5 and 7 but also against 17beta-HSD 1 of several other species including marmoset, pig, mouse, and rat. The latter are used in the processes of pharmacophore screening. We present the quantification of inhibitor preferences between human and animal models. Profound differences in the susceptibility to inhibition of steroid conversion among all 17beta-HSDs analyzed were observed. Especially, the rodent 17beta-HSDs 1 were significantly less sensitive to inhibition compared to the human ortholog, while the most similar inhibition pattern to the human 17beta-HSD 1 was obtained with the marmoset enzyme. Molecular docking experiments predicted estrone as the most potent inhibitor. The best performing compound in enzymatic assays was also highly ranked by docking scoring for the human enzyme. However, species-specific prediction of inhibitor performance by molecular docking was not possible. We show that experiments with good candidate compounds would out-select them in the rodent model during preclinical optimization steps. Potentially active human-relevant drugs, therefore, would no longer be further developed. Activity and efficacy screens in heterologous species systems must be evaluated with caution.
authors.affiliation: Helmholtz Zentrum München, Institute of Experimental Genetics, Genome Analysis Center, Neuherberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Möller
authors.forename: Bettina
authors.initials: B
authors.lastname: Husen
authors.forename: Dorota
authors.initials: D
authors.lastname: Kowalik
authors.forename: Leena
authors.initials: L
authors.lastname: Hirvelä
authors.forename: Dariusz
authors.initials: D
authors.lastname: Plewczynski
authors.forename: Leszek
authors.initials: L
authors.lastname: Rychlewski
authors.forename: Josef
authors.initials: J
authors.lastname: Messinger
authors.forename: Hubert
authors.initials: H
authors.lastname: Thole
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D013045:Species Specificity; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human