Plavša-Puž Jovana J, Brynda Jiří, Ajduković Jovana J, Bekić Sofija, Ćelić Andjelka, Řezáčová Pavlína, Škerlová Jana, Petri Edward
Department of Biology and Ecology, University of Novi Sad, Novi Sad, Serbia.
Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic.
J Enzyme Inhib Med Chem. 2025 Dec;40(1):2551979. doi: 10.1080/14756366.2025.2551979. Epub 2025 Sep 4.
Human aldo-keto reductase 1C3 (AKR1C3) is a steroid modifying enzyme involved in cancer progression. Here, A-ring modified 17α-picolyl and 17()-picolinylidene androstane derivatives are shown to inhibit AKR1C3 activity . None of the androstane derivatives have off-target affinity for the androgen receptor, based on a fluorescence assay in yeast cells. The X-ray structure of AKR1C3 in complex with the strongest inhibitor, a 17α-picolyl androstane with a C3-oxime modification, was determined at 1.7 Å resolution. Based on this crystal structure and molecular docking, inhibition of AKR1C3 by the 17α-picolyl or 17()-picolinylidene derivatives depends on interactions between the C3 modification and the NADP cofactor, while the C17α-picolyl or C17-picolinylidene group anchors the inhibitor to AKR1C3. Because one AKR1C3 inhibitor identified here was also previously reported to inhibit CYP17, it may be possible for future researchers to design dual AKR1C3/CYP17 inhibitors based on a steroid scaffold for potential treatment of advanced prostate cancers.
人醛酮还原酶1C3（AKR1C3）是一种参与癌症进展的甾体修饰酶。在此，A环修饰的17α-吡啶甲基和17（）-吡啶亚甲基雄甾烷衍生物被证明可抑制AKR1C3活性。基于酵母细胞中的荧光测定，所有雄甾烷衍生物对雄激素受体均无脱靶亲和力。以1.7Å的分辨率测定了AKR1C3与最强抑制剂（一种具有C3肟修饰的17α-吡啶甲基雄甾烷）复合物的X射线结构。基于该晶体结构和分子对接，17α-吡啶甲基或17（）-吡啶亚甲基衍生物对AKR1C3的抑制作用取决于C3修饰与NADP辅因子之间的相互作用，而C17α-吡啶甲基或C17-吡啶亚甲基基团则将抑制剂锚定在AKR1C3上。由于此处鉴定出的一种AKR1C3抑制剂先前也被报道可抑制CYP17，因此未来的研究人员有可能基于甾体支架设计双AKR1C3/CYP17抑制剂，用于晚期前列腺癌的潜在治疗。
