Abstract
Steroid-related cancers can be treated by inhibitors of steroid metabolism. In searching for new inhibitors of human 17beta-hydroxysteroid dehydrogenase type 1 (17β-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 17β-HSD types and species. Compounds were tested for specificity in vitro not only towards recombinant human 17β-HSD types 1, 2, 4, 5 and 7 but also against 17β-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 17β-HSDs analyzed were observed. Especially, the rodent 17β-HSDs 1 were significantly less sensitive to inhibition compared to the human ortholog, while the most similar inhibition pattern to the human 17β-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.
Highlights
Human diseases could be treated by selective manipulation of pathways involved in their pathogenesis
Several druggable targets were defined in humans [1,2] including steroid metabolizing enzymes like 17b-hydroxysteroid dehydrogenases (17b-HSDs) controlling the biological potency of steroid hormones by redox reactions at position 17 of the steroid scaffold [3,4,5,6,7]. 17bHSDs belong to the short-chain dehydrogenase/reductase superfamily (SDR) [8], except for 17b-HSD type 5 which is a member of aldoketoreductase (AKR) superfamily [9]
We recently contributed to this field by a development of novel effective inhibitors of this enzyme by exploring modifications at positions 2 or 15 of estrone [24] and designing fluorine derivatives of estrone [25]
Summary
Human diseases could be treated by selective manipulation of pathways involved in their pathogenesis. Several druggable targets were defined in humans [1,2] including steroid metabolizing enzymes like 17b-hydroxysteroid dehydrogenases (17b-HSDs) controlling the biological potency of steroid hormones by redox reactions at position 17 of the steroid scaffold [3,4,5,6,7]. Since the observation of the prognostic value of 17b-HSDs in breast or prostate cancers [10,11,12,13,14] the research on these enzymes included development of specific inhibitors [15,16,17,18,19,20,21,22,23]. It was assumed that in hormonedependent cancers an inhibitor of conversion of estrone to estradiol by 17b-HSD 1 would deplete the biologically active hormone estradiol from the signal transduction pathway and by that constrain cell proliferation in breast cancer or endometriosis. We recently contributed to this field by a development of novel effective inhibitors of this enzyme by exploring modifications at positions 2 or 15 of estrone (compounds 1, 2 and 3 in this study) [24] and designing fluorine derivatives of estrone [25]
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