Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor

Abstract

Type 5 17β-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Δ4-androstene-3,17-dione and 5α-androstane-3,17-dione to testosterone (T) and 5α-dihydrotestosterone, respectively, in castration resistant prostate cancer (CRPC). In CRPC, AKR1C3 is implicated in drug resistance, and enzalutamide drug resistance can be surmounted by indomethacin a potent inhibitor of AKR1C3. We examined a series of naproxen analogues and find that (R)-2-(6-methoxynaphthalen-2-yl)butanoic acid (in which the methyl group of R-naproxen was replaced by an ethyl group) acts as a potent AKR1C3 inhibitor that displays selectivity for AKR1C3 over other AKR1C enzymes. This compound was devoid of inhibitory activity on COX isozymes and blocked AKR1C3 mediated production of T and induction of PSA in LNCaP-AKR1C3 cells as a model of a CRPC cell line. R-Profens are substrate selective COX-2 inhibitors and block the oxygenation of endocannabinoids and in the context of advanced prostate cancer R-profens could inhibit intratumoral androgen synthesis and act as analgesics for metastatic disease.

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

“…S1; ref. 40). We also examined the mode of action of KV-37 in androgen-dependent 22Rv1 cells (high AKR1C3 expression) and LNCaP cells (low AKR1C3 expression).…”

“…Systems (200 mL) containing 100 mmol/L potassium phosphate (pH 7.0), 0.9 mmol/L NADPH, 1.2 to 40 mmol/L 4-androstene-3,17-dione (D4-AD; containing 2.6 nmol/L [ 3 H]-4-androstene-3,17-dione), KV-37 (0-10 mmol/L), and 0.3 to 10 mmol/L inhibitor plus 1.65 mmol/L AKR1C3 were incubated at 37 C, and samples were prepared as previously reported (40). Quantification of the individual steroid analytes was achieved by integrating the radioactivity corresponding to each peak in the radiochromatogram and representing the radioactivity as a percentage of the total corrected cpm for the organic fraction from which it was derived.…”

Aldo-Keto Reductase Regulation by the Nrf2 System: Implications for Stress Response, Chemotherapy Drug Resistance, and Carcinogenesis

“…26,31,122 Extensive drug discovery programs exist for the development of AKR1C3 inhibitors for hormone-dependent malignancies. 123–130 The fact that each of these genes are regulated by the Keap1/Nrf2 pathway suggests that Nrf2 activators may have unintended consequences for steroid hormone receptor occupancy and hence steroid hormone action in both physiology and hormone-dependent malignancies.…”

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

“…Patent WO2012122208 was issued for N -phenylaminobenzoates represented by 24 and patent WO2013059245 was issued for indo-methacin analogs, represented by 20 – 22 [50,51]. This was subsequently followed by patent W02017070448 for β-naphthylacetic acids ( R -naproxen analogs), 26 [52]. In each case, the NSAID analogs were subjected to medicinal chemistry optimization to remove structural features required for inhibition of COX-1 and COX-2 while inhibition of AKR1C3 was retained.…”

“…For the aryl propionic acids 25 , β-naphthylacetic acids in which the stereochemistry at the alkyl substituent at the alpha carbon was changed from S- to R- were sufficient to abolish COX-1 and COX-2 inhibition but retain AKR1C3 inhibition; compounds such as 26 are disclosed in WO2017070448 (Figure 4) [52]. …”