A Challenge for Medicinal Chemistry by the 17Β-Hydroxysteroid Dehydro
Total Page：16
File Type：pdf, Size：1020Kb
Send Orders of Reprints at [email protected] 1164 Current Topics in Medicinal Chemistry, 2013, 13, 1164-1171 A Challenge for Medicinal Chemistry by the 17-hydroxysteroid Dehydro- genase Superfamily: An Integrated Biological Function and Inhibition Study S.-X. Lina,b, D. Poiriera and J. Adamskic,d.e aLaboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire (CHU) de Quebec Research Center (CHUL) and Laval University, Québec City, Québec, G1V4G2, Canada; bWHO Collaborating Center for Re- search in Human Reproductive Health, Shanghai, 200031, China; cHelmholtz Zentrum München, Institute of Experi- mental Genetics, Genome Analysis Center, 85764 Neuherberg, Germany; dLehrstuhl für Experimentelle Genetik, Tech- nische Universität München, 85350 Freising-Weihenstephan, Germany; eGerman Center for Diabetes Research (DZD), 85764 Neuherberg, Germany Abstract: Members of the 17-hydroxysteroid dehydrogenase (17-HSD) superfamily perform distinct multiple catalyses by the same enzyme, apparently contradictory to the long-held beliefs regarding the high specificity of enzymes. Surpris- ingly, these multi-catalyses can combine synergistically in vitro and in vivo and their dysfunction may result in the stimu- lation of breast or prostate cancer. 17-HSD1 possesses high estrogen activation activity, while its androgen inactivation is significant for decreasing the week concentration of dihydrotestosterone (DHT) in breast cancer cells, an important fac- tor for cell proliferation. 17-HSD5 can also carry out multiple catalyses in hormone-dependent cancer cells. In addition to 17-HSDs 1 and 5 some other family members possess such dual-activity as well, and their inhibition decreases hor- mone-dependent cancer proliferation. The multi-specificity of 17-HSD1 is structurally based on the pseudo-symmetric androgens that can accommodate the narrow enzyme substrate tunnel by both normal and alternative binding. The atypical family member 17-HSD5 possesses a spacious binding site, which is accessible to several substrates. Expression of 17- HSD1 can also control other estrogen-responsive elements such as pS2, and can regulate steroid-hormone receptors. The fundamental involvement of 17-HSD1 in catalysis and gene regulation underlies its close relationship to breast cancer, attributable to its long evolutionary process. These observations stimulated detailed study of steroid-converting enzyme inhibition. The most significant efforts in designing 17-HSD1 inhibitors in decades have progressed through structure ac- tivity relationship studies supported by the availability of both small and protein molecule structures, with the elimination of residual estrogenic activity in the inhibitors. The first non-estrogenic inhibitors of 17-HSD1 to show activity in vivo (breast cancer animal model) are now reported. Keywords: 17-hydroxysteroid dehydrogenase (17-HSD) superfamily, estrogen-dependent breast cancer, pre-receptor modu- lation of steroid hormone action, rational design of inhibitors, structure-activity relationship. INTRODUCTION [15], can generate many useful data for which it would be.time-consuming and costly to obtain by experiments During the last two decades or so, considerable pro- alone Actually, these data, combined with the information gresses have been made in developing various cheminfor- derived from the structural bioinformatics tools [see, e.g., matics methods or tools for new drug target exploration, reference 16] and structural cheminformatics tools [see, e.g., such as those for identifying predicting the network of sub- references 17-19] can timely provide very useful insights for strate-enzyme-product triads [1], identify recombination both medicinal chemistry research and drug development. spots [2], identify nuclear receptors and their types [3], iden- The use of structure-activity relationship can be considered tifying HIV cleavage sites in proteins [4-6], predicting including both protein and small molecule structures [20, GPCRs and their types [7], predicting proteases and their 21]. The current review is to summarize the progresses in types [8], identifying colorectal cancer related genes [9], studying the 17-hydroxysteroid dehydrogenase (17-HSD) classifying hepatocellular cirrhosis and carcinoma [10], pre- superfamily characterized by an integrated biological func- dicting secretory proteins of malaria parasite [11], predicting tion and inhibition study to further stimulate the develop- protein subcellular locations [12], QSAR [13, 14], and a se- ment of cheminformatics in this area. ries of powerful web-server predictors listed in Table 3 of ENZYMOLOGY IN 17-HSD FAMILY *Address correspondence to this author at the Laboratory of Molecular Enzyme-mediated catalysis characterized by kinetic Endocrinology and Oncology, Centre Hospitalier Universitaire (CHU) de Quebec Research Center (CHUL) 2705, boulevard Laurier Québec City, properties, substrate specificity, and varying mechanisms of Québec, G1V4G2, Canada; Tel/Fax: 1-4186542296/6542761; reaction have been studied for more than a century providing E-mail: [email protected] the most precise information regarding biological processes 1568-0266/13 $58.00+.00 © 2013 Bentham Science Publishers A Challenge for Medicinal Chemistry by the 17-hydroxysteroid Dehydrogenase Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 10 1165 to date. This is pivotal for the understanding of cellular ho- are unknown. Steroid conversion capability apparently meostasis, response to environmental challenge, and mecha- evolved as a multi-step process and has its roots in retinoid, nisms of disease. Recent studies of the biological function of fatty acyl, or acetate converting enzymes [31-33]. members of the 17-HSD superfamily revealed that their Our knowledge of enzyme catalysis often comes from activities and specificities can vary extensively by several assays with purified homogeneous enzymes (e.g. 17-HSD1 orders of magnitude toward different steroids, and their and 5)[24-35]. Enzymes may display specificities at varying multi-specificities can be significant. Not only can some levels toward different substrates with accompanying con- critical enzymes affect cancer cell proliferation, but their formational rearrangements in the binding site, thus expand- expression regulates the transcription and expression of other ing their functional involvement. In vitro study and animal genes, thereby demonstrating pivotal biological roles. This models of several enzymes contributed extensively to under- review will provide a succinct presentation of several func- standing the systemic or physiological effects of the enzymes tional aspects of 17-HSDs to illustrate the scope of the ca- (e.g. yeast complementation assay of 17-HSD7, siRNA- pacity of these enzymes and their inhibition. mediated silencing of 17-HSD1, transgenic 17-HSD1, or At least 14 different mammalian 17-HSDs have been knock-out 17-HSD types 2 and 7) [36-40]. identified [22-25], of which 12 members have been found in On the basis of substrate specificity, 17-HSDs can be humans [22, 26]. Their kinetic parameters (substrate speci- assigned to two groups. The first comprises steroid- ficity, reaction direction, cofactor dependence), tissue distri- converting enzymes and includes 17-HSDs types 1–3. The bution, and sub-cellular localization differ significantly. The second constitutes steroid-converting enzymes, and those 17-HSDs stereo-specifically interconvert ketones and their interacting with acyl-CoAs (17-HSDs 4, 8, 10, and 12), bile corresponding secondary alcohols using NAD(P)H or acids (17-HSDs 4 and 10), and retinoids (17-HSDs 6 and NAD(P)+ as cofactor, with reduction or oxidation as their 9) [41]. Most of the 17-HSDs are members of the function- respective principal reaction under physiological conditions. ally promiscuous SDR (short chain dehydrogenase reduc- The 17-HSD enzymes are molecular switches in pre- tase) group [42], except for 17-HSD5, which is an AKR receptor modulation of steroid hormone action for both ge- (aldo-keto reductase) enzyme [43]. nomic (nuclear mediated) and non-genomic pathways like those of GPCR (G protein-coupled receptor) [26-29]. Oxida- The reaction mechanisms of 17-HSDs are different from tion of the C17 hydroxyl of dihydrotestosterone, testoster- each other, which is consistent with their modest sequence one, or 17-estradiol, reduces the potency of these steroids. identity and subdivision into different protein families: SDR Similarly, the reduction of the C17-keto group of 5alpha- and AKR. Nevertheless, they share the common feature of a androstane-3,17-dione, 4-androstene-3,17-dione, or estrone reversible hydride transfer from NADPH to a ketosteroid, or yields the biologically active steroid forms (Fig. 1). Further- hydride transfer from a hydroxysteroid to NAD+ [44, 45]. more, reductive 17-HSDs catalyze the final step in the bio- The 17-HSDs of the SDR-family share conserved amino synthesis of the most active estrogens (estradiol and 5- acids that constitute a catalytic triad essential for steroid androstene-3,17-diol) and androgens (testosterone and conversion: Ser142, Tyr155, and Lys159 (numbering for dihydrotestosterone) [30]. 17-HSD1) [46, 47]. Further interactions with a water mole- cule and Asn114 are critical for enzyme activity [48, 49]. 17-HSDs are involved in the etiology of several human diseases. Either loss-of-function (e.g. loss of 17-HSD4 in lethal human D-specific bifunctional protein deficiency), or over-expression (e.g. 17-HSD1 in