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

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.

5β-羟基类固醇脱氢酶，醛酮还原酶1C3（AKR1C3）在去势抵抗性前列腺癌（CRPC）中将Δ4-雄甾烯-3,17-二酮和5α-雄甾烷-3,17-二酮分别转化为睾酮（T）和5α-二氢睾酮。在CRPC中，AKR1C3与药物耐药性相关，而恩杂鲁胺的耐药性可以通过强力抑制AKR1C3的吲哚美辛来克服。本研究考察了一系列萘普生类似物，发现（R）-2-（6-甲氧基萘-2-基）丁酸（其中R-萘普生的甲基被乙基取代）是一种高效的AKR1C3抑制剂，对AKR1C3具有选择性，而对其他AKR1C酶则无抑制作用。该化合物对COX同工酶无抑制作用，并且能够阻断AKR1C3介导的睾酮产生和诱导PSA在LNCaP-AKR1C3细胞中的产生，该细胞是CRPC细胞系的一个模型。R-Profens是底物选择性的COX-2抑制剂，可阻断内源性大麻素的氧化，在晚期前列腺癌的背景下，R-Profens能够抑制肿瘤内雄激素合成，并作为转移性疾病的治疗性镇痛剂。