02 BOOK OF ABSTRACTS .indd

New inhibitors of human hydroxysteroiddehydrogenases
AKR1C1 and AKR1C3: potential agents
for treatment of hormone dependent forms of cancer
Petra Bro`i~ 1 , Tea Lani{nik Ri`ner 1 , Stanislav Gobec 2
1
Institute of Biochemistry, Medical Faculty, University of Ljubljana, Vrazov trg 2, 1000
Ljubljana, Slovenia; 2 Faculty of Pharmacy, University of Ljubljana, A{ker~eva 7, 1000
Ljubljana, Slovenia
Hydroxysteroid dehydrogenases AKR1C1 and AKR1C3, members of the aldoketo
reductase superfamily, interconvert the active and inactive forms of steroid
hormones. In this manner they are involved in hormonal regulation and function
in human and represent interesting targets for development of drugs for treatment
of hormone dependent forms of cancer like prostate cancer, breast cancer and
endometrial cancer. Recently, non-steroidal anti-inflammatory drugs (NSAIDs) like
indomethacin, flufenamic acid and related compounds have been identified as
potent inhibitors of AKR1C3 and moderate inhibitors of AKR1C1. We have examined
the inhibitory potencies of frequently used NSAIDs that have not been evaluated
yet. In order to obtain more information about structure-activity relationship and
to identify compounds with new scaffolds a series of compounds designed on the
basis of NSAIDs was synthesized and tested for their inhibitory activity against the
recombinant AKR1C1 and AKR1C3. We have shown that it is possible to prepare
selective inhibitors of either AKR1C1 or AKR1C3. IC 50
values that were determined for
compounds with promising inhibitory potency were in low micromolar range which
indicates that new leads were identified and can be used as a good starting point for
future design and synthesis of new inhibitors. New and improved inhibitors would
be important for treatment of hormone-dependent cancers, gastrointestinal tumors,
p4
leukaemia, depression, for maintaining pregnancy and other conditions involving
AKR1C1 and AKR1C3.
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