TY - JOUR
T1 - Screening baccharin analogs as selective inhibitors against type 5 17β-hydroxysteroid dehydrogenase (AKR1C3)
AU - Zang, Tianzhu
AU - Verma, Kshitij
AU - Chen, Mo
AU - Jin, Yi
AU - Trippier, Paul C.
AU - Penning, Trevor M.
N1 - Funding Information:
The following authors declare no conflict of interest (T.Z., K.V., M.C., Y.J.). Dr. Trippier reports non-financial support from Kimax (Kimble Chase), during the conduct of the study; and Dr. Penning reports grants from the National Cancer Institute, National Institute of Environmental Health Sciences, and from the Prostate Cancer Foundation, during the conduct of the study; and consultant fees from Tokai Pharmaceuticals, outside the submitted work. In addition, Dr. Penning has a patent No PCT/US12/33199 pending, and a patent No. PCT/US1242-96 pending and is Founder, Penzymes LLC devoted to developing inhibitors of AKR1C enzymes involved in hormone biosynthesis in steroid hormone dependent malignancies.
Funding Information:
This work was supported by the NCI and NIEHS ( R01-CA90744 and P30-ES013508 to T.M.P) from the National Institutes of Health and by Texas Tech University Health Sciences Center (P.C.T).
Publisher Copyright:
© 2014 Elsevier Ireland Ltd. All rights reserved.
PY - 2015/6/5
Y1 - 2015/6/5
N2 - Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase, is a downstream steroidogenic enzyme and converts androgen precursors to the potent androgen receptor ligands: testosterone and 5α-dihydrotestosterone. Studies have shown that AKR1C3 is involved in the development of castration resistant prostate cancer (CRPC) and that it is a rational drug target for the treatment of CRPC. Baccharin, a component of Brazilian propolis, has been observed to exhibit a high inhibitory potency and selectivity for AKR1C3 over other AKR1C isoforms and is a promising lead compound for developing more potent and selective inhibitors. Here, we report the screening of fifteen baccharin analogs as selective inhibitors against AKR1C3 versus AKR1C2 (type 3 3α-hydroxysteroid dehydrogenase). Among these analogs, the inhibitory activity and selectivity of thirteen compounds were evaluated for the first time. The substitution of the 4-dihydrocinnamoyloxy group of baccharin by an acetate group displayed nanomolar inhibitory potency (IC50: 440 nM) and a 102-fold selectivity over AKR1C2. By contrast, when the cinnamic acid group of baccharin was esterified, there was a dramatic decrease in potency and selectivity for AKR1C3 in comparison to baccharin. Low or sub-micromolar inhibition was observed when the 3-prenyl group of baccharin was removed, and the selectivity over AKR1C2 was low. Although unsubstituted baccharin was still the most potent (IC50: 100 nM) and selective inhibitor for AKR1C3, these data provide structure-activity relationships required for the optimization of new baccharin analogs. They suggest that the carboxylate group on cinnamic acid, the prenyl group, and either retention of 4-dihydrocinnamoyloxy group or acetate substituent on cinnamic acid are important to maintain the high potency and selectivity for AKR1C3.
AB - Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase, is a downstream steroidogenic enzyme and converts androgen precursors to the potent androgen receptor ligands: testosterone and 5α-dihydrotestosterone. Studies have shown that AKR1C3 is involved in the development of castration resistant prostate cancer (CRPC) and that it is a rational drug target for the treatment of CRPC. Baccharin, a component of Brazilian propolis, has been observed to exhibit a high inhibitory potency and selectivity for AKR1C3 over other AKR1C isoforms and is a promising lead compound for developing more potent and selective inhibitors. Here, we report the screening of fifteen baccharin analogs as selective inhibitors against AKR1C3 versus AKR1C2 (type 3 3α-hydroxysteroid dehydrogenase). Among these analogs, the inhibitory activity and selectivity of thirteen compounds were evaluated for the first time. The substitution of the 4-dihydrocinnamoyloxy group of baccharin by an acetate group displayed nanomolar inhibitory potency (IC50: 440 nM) and a 102-fold selectivity over AKR1C2. By contrast, when the cinnamic acid group of baccharin was esterified, there was a dramatic decrease in potency and selectivity for AKR1C3 in comparison to baccharin. Low or sub-micromolar inhibition was observed when the 3-prenyl group of baccharin was removed, and the selectivity over AKR1C2 was low. Although unsubstituted baccharin was still the most potent (IC50: 100 nM) and selective inhibitor for AKR1C3, these data provide structure-activity relationships required for the optimization of new baccharin analogs. They suggest that the carboxylate group on cinnamic acid, the prenyl group, and either retention of 4-dihydrocinnamoyloxy group or acetate substituent on cinnamic acid are important to maintain the high potency and selectivity for AKR1C3.
KW - Androgen
KW - Androgen receptor signaling
KW - Castration resistant prostate cancer
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U2 - 10.1016/j.cbi.2014.12.015
DO - 10.1016/j.cbi.2014.12.015
M3 - Article
C2 - 25555457
AN - SCOPUS:84939990776
SN - 0009-2797
VL - 234
SP - 339
EP - 348
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
ER -