Pramanik Jhuma, Shaji Sanu Korumadathil, Zaman Megan, Brown Bethany, Zhang Baojie, Yamashita-Kanemaru Yumi, Homer Natalie Z M, Hussein Hosni A M, Zhao Qiuchen, Okkenhaug Klaus, Roychoudhuri Rahul, Mukhopadhyay Abhik, Mahata Bidesh
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
Mass Spectrometry Core, Edinburgh Clinical Research Facility, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
iScience. 2025 Apr 18;28(5):112488. doi: 10.1016/j.isci.2025.112488. eCollection 2025 May 16.
Steroid hormones regulate cell physiology and immune function, with dysregulated steroidogenesis promoting cancer progression by supporting tumor growth and suppressing anti-tumor immunity. Targeting CYP11A1, the first and rate-limiting enzyme in steroid biosynthesis, has shown promise in cancer therapy, but safe and effective inhibitors remain an unmet need. Undertaking structure-based drug repurposing approach, we found posaconazole as an inhibitor of CYP11A1. The docking pose analysis showed that posaconazole can form multiple hydrogen bonds and hydrophobic interactions with the key residues at the binding site and the cofactor, stabilizing the protein-ligand complex. We validated its inhibition efficiency in cell-based assays. In a mouse model of lung metastasis, we demonstrated that posaconazole restricts metastasis by stimulating anti-tumor immunity. These findings highlight posaconazole's potential as a research tool to study steroidogenesis and as a candidate for further preclinical and clinical evaluation in pathologies associated with local steroidogenesis, such as steroidogenic tumors.
类固醇激素调节细胞生理和免疫功能，类固醇生成失调通过支持肿瘤生长和抑制抗肿瘤免疫促进癌症进展。靶向CYP11A1（类固醇生物合成中的首个限速酶）在癌症治疗中显示出前景，但安全有效的抑制剂仍未得到满足。通过基于结构的药物重新利用方法，我们发现泊沙康唑是CYP11A1的抑制剂。对接构象分析表明，泊沙康唑可与结合位点的关键残基和辅因子形成多个氢键和疏水相互作用，稳定蛋白质-配体复合物。我们在基于细胞的试验中验证了其抑制效率。在肺转移小鼠模型中，我们证明泊沙康唑通过刺激抗肿瘤免疫来限制转移。这些发现突出了泊沙康唑作为研究类固醇生成的研究工具的潜力，以及作为与局部类固醇生成相关的病理（如类固醇生成肿瘤）进一步临床前和临床评估候选药物的潜力。
