The structural basis of aldo-keto reductase 1C3 inhibition by 17α-picolyl and 17(E)-picolinylidene androstane derivatives.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jovana J Plavša-Puž, Jiří Brynda, Jovana J Ajduković, Sofija Bekić, Andjelka Ćelić, Pavlína Řezáčová, Jana Škerlová, Edward Petri
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引用次数: 0

Abstract

Human aldo-keto reductase 1C3 (AKR1C3) is a steroid modifying enzyme involved in cancer progression. Here, A-ring modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives are shown to inhibit AKR1C3 activity in vitro. 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(E)-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.

17α-吡咯酰基和17(E)-吡咯酰基雄甾衍生物抑制醛酮还原酶1C3的结构基础。
人醛酮还原酶1C3 (AKR1C3)是一种参与癌症进展的类固醇修饰酶。研究表明,a环修饰的17α-吡啶基和17(E)-吡啶-雄甾烷衍生物在体外抑制AKR1C3活性。根据酵母细胞的荧光测定,没有雄甾衍生物对雄激素受体具有脱靶亲和力。在1.7 Å分辨率下测定了AKR1C3与最强抑制剂(c3 -肟修饰的17α-吡啶雄甾烷)配合物的x射线结构。基于这种晶体结构和分子对接,17α-吡啶基或17(E)-吡啶基衍生物对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c17 α-吡啶基或c17 -吡啶基将抑制剂锚定在AKR1C3上。由于本研究发现的一种AKR1C3抑制剂先前也被报道抑制CYP17,因此未来的研究人员可能会基于类固醇支架设计双重AKR1C3/CYP17抑制剂,用于晚期前列腺癌的潜在治疗。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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