Wróbel Tomasz M, Grudzińska Angelika, Yakubu Jibira, du Toit Therina, Sharma Katyayani, Harrington Jeremiah C, Björkling Fredrik, Jørgensen Flemming Steen, Pandey Amit V
Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, Lublin, Poland.
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
J Enzyme Inhib Med Chem. 2025 Dec;40(1):2463014. doi: 10.1080/14756366.2025.2463014. Epub 2025 Feb 14.
Prostate cancer (PCa) is one of the most prevalent malignancies affecting men worldwide, and androgen deprivation therapy (ADT) is a primary treatment approach. CYP17A1 inhibitors like abiraterone target the steroidogenic pathway to reduce androgen levels, but their clinical efficacy is limited by drug resistance and adverse effects. This study reports the synthesis and evaluation of novel CYP17A1 inhibitors derived from a previously identified hit compound. Several analogs were synthesised, including an unexpected di-cyano derivative, which demonstrated increased potency against CYP17A1 compared to abiraterone. Biological assays revealed that these compounds significantly inhibited CYP17A1 enzymatic activity and altered steroid biosynthesis. Among the newly synthesised inhibitors, compound showed the highest potency (IC = 4 nM) and the related compound presented a template for further development. A combined docking and molecular dynamics approach was used to identify the possible target binding modes of the compounds.
前列腺癌（PCa）是全球影响男性的最常见恶性肿瘤之一，雄激素剥夺疗法（ADT）是主要的治疗方法。像阿比特龙这样的CYP17A1抑制剂靶向类固醇生成途径以降低雄激素水平，但其临床疗效受到耐药性和不良反应的限制。本研究报告了源自先前鉴定的活性化合物的新型CYP17A1抑制剂的合成和评估。合成了几种类似物，包括一种意外的二氰基衍生物，与阿比特龙相比，它对CYP17A1表现出更高的效力。生物学测定表明，这些化合物显著抑制CYP17A1酶活性并改变类固醇生物合成。在新合成的抑制剂中，化合物 显示出最高的效力（IC = 4 nM），相关化合物 为进一步开发提供了模板。采用对接和分子动力学相结合的方法来确定化合物可能的靶标结合模式。
