Book of abstract 2008

New inhibitors of steroid metabolizing enzymes as potential anticancer
agents
Petra Brožič1, Samo Turk2, Andreja Kovač2, Matej Sova2, Katja Kristan1, Tea Lanišnik
Rižner1, Stanislav Gobec2
1Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana,
Slovenia; 2Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
Androgens and estrogens increase the number of cell divisions and the opportunity
for random genetic errors and are thus involved in carcinogenesis of hormone related
cancers. Pre-receptor regulatory enzymes interconvert the active forms of hormones
with high affinities to corresponding receptors with their less active forms with very
low affinities (1). These enzymes represent interesting targets for development of new
drugs for prevention and treatment of conditions caused by disturbed hormone action.
We focused our attention to hydroxysteroid dehydrogenases (HSD), which are enzymes
that act as molecular switches (2). We study human recombinant AKR1C1, AKR1C3
and 17beta-HSD type 1. AKR1C1 reduces a potent progesterone to a weak 20alphahydroxyprogesterone,
while AKR1C3 reduces a weak androgen androstenedione to
a potent testosterone. Both AKR1C3 and 17beta-HSD type 1 convert weak estrogen
estrone to a potent estradiol (3, 4). The recombinant enzymes AKR1C1 and AKR1C3
were isolated and our in-house bank of compounds was screened for potential inhibitors.
Automated docking was used to explain the possible binding orientation of best inhibitors
within the active site. Three groups of compounds were shown to potently inhibit
AKR1C1 and AKR1C3: phytoestrogens (5,6), cinnamic acids (7) and nonsteroidal antiinflammatory
drugs and their analogues (8). To search for potential inhibitors of 17beta-
HSD type 1 we used the easily available model enzyme 17beta-HSD from the fungus
Cochliobolus lunatus. We found that this enzyme is inhibited by phytoestrogens, cinnamic
acid esters and cinnamamides (9). In addition to screening and analogue-based approach,
structure-based virtual high-throughput screening is performed to discover new small
molecule inhibitors of all
l9
enzymes under investigation.
References:
1. Henderson, B.E.; Feigelson, H.S. Carcinogenesis, 2000, 21, 427-433.
2. Nobel, S.; Abrahmsen, L.; Oppermann, U. Eur. J. Biochem., 2001, 268, 4113-4125.
3. Penning, T. M.; Burczynski, M.E.; Jez, M.E.; Hung, C.F.; Lin, H.K.; Ma, H.; Moore, M.; Palackal, N.;
Ratnam K. Biochem. J., 2000, 351, 67-77.
4. Penning, T.M. Endocr. Rev., 1997, 18, 281-305.
5. Brožič, P.; Šmuc, T.; Gobec, S.; Lanišnik Rižner, T. Mol. Cell. Endocrinol., 2006, 259, 30-42.
6. Brožič, P.; Golob, B.; Gomboc, N.; Lanišnik Rižner, T.; Gobec, S. Mol. Cell. Endocrinol., 2006, 248,
233-235.
7. Brožič, P.; Šmuc, T.; Gobec, S.; Lanišnik Rižner, T. Enzymology and molecular biology of carbonyl metabolism
13. Purdue: Purdue University, 2007, 252-262.
8. Gobec, S.; Brožič, P.; Lanišnik Rižner, T. Bioorg. Med. Chem. Lett., 2005, 15, 5170-5175.
9. Sova, M.; Perdih, A.; Kotnik, M.; Kristan, K.; Lanišnik-Rižner, T.; Šolmajer, T.; Gobec, S. Bioorg. Med.
Chem..2006, 14, 7404-7418.
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