Screening baccharin analogs as selective inhibitors against type 5 17β-hydroxysteroid dehydrogenase (AKR1C3)

Abstract

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.

Selective AKR1C3 Inhibitors Potentiate Chemotherapeutic Activity in Multiple Acute Myeloid Leukemia (AML) Cell Lines

“…The inhibitory activities of the synthesized baccharin derivatives against AKR1C3 and the highly homologous isozyme AKR1C2 were determined (Table 1). 21 Synthetic baccharin (1) exhibited potency for AKR1C3 inhibition (pIC 50 = 7.0) and excellent selectivity (510-fold) as expected. The para-amide derivative (2) retained some potency and selectivity (pIC 50 = 6.4 with 89-fold selectivity) for AKR1C3.…”

AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells

“…Inhibitors of AKR1C3 from various structural classes [flavones (30), jasmonates (31), and NSAIDS (23, 33)] have previously been described. We adopted a cinnamic acid derivative "baccharin" and conducted structure-activity relationship (SAR) studies to identify lead AKR1C3 inhibitors (37,38). The cinnamic acid derivative KV-37 ( Fig.…”

“…1A; refs. [36][37][38], in androgen-sensitive prostate cancer cell lines and a xenograft model. We have previously reported AKR1C3 inhibitors that act synergistically with etoposide and daunorubicin as chemotherapeutic agents in a panel of leukemia cell lines (38).…”

Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review

“…Natural products such as baccharin analogs 29 (from the Brazilian propolis) have also be claimed as AKR1C3 inhibitors, and these derivatives contain a phenolic cinammic acid substituted with an isopropyl group and a phenylpropionic ester [60,61]. However, these compounds are likely to hydrolyze in vivo to the corresponding alcohol and acid.…”