Irham Lalu Muhammad, Adikusuma Wirawan, Afief Arief Rahman, Khairi Sabiah, Chong Rockie, Mufidah Syarifatul, Satria Rahmat Dani, Mugiyanto Eko, Darmawi Darmawi, Amukti Danang Prasetyaning, Wirsahada Brilliant Citra, Philothra Petrina Theda, Jaya Indra
Faculty of Pharmacy, Universitas Ahmad Dahlan, Yogyakarta, 55166, Indonesia.
Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand.
BMC Pharmacol Toxicol. 2025 Aug 5;26(1):145. doi: 10.1186/s40360-025-00983-3.
Prostate cancer remains a prevalent global health challenge, with limited treatment options for advanced stages. There is a critical need to identify effective therapies through systematic integration of genomic and biological data.
We analyzed 10,911 single nucleotide polymorphisms (SNPs) in 554 genes from genome- and phenome-wide association studies to identify biological risk genes for prostate cancer. Bioinformatic analysis was used to map these genes to key pathways and potential drug targets. Drug repurposing opportunities were assessed through Connectivity Map (CMap) transcriptomic signature analysis in the PC3 prostate cancer cell line, with additional molecular docking studies to evaluate drug-target interactions.
We identified 77 prostate cancer-associated genes. Drug repurposing analysis revealed 59 drugs targeting 13 genes, including 11 approved for prostate cancer and 22 in clinical or preclinical development. Notably, 26 candidate drugs had not been previously linked to prostate cancer. CMap analysis prioritized five candidates: estradiol-benzoate and estradiol-cypionate (targeting ESR2), which showed the highest CMap scores, danazol and oxymetholone (targeting AR), and selumetinib (targeting MAP2K1/MEK), each demonstrating potential to modulate key pathways in prostate cancer. Molecular docking analysis further supported these findings, revealing that estradiol-benzoate and estradiol-cypionate have strong predicted binding affinities for ESR2, while selumetinib robustly interacts with MAP2K1. Conversely, danazol and oxymetholone displayed weaker predicted binding, suggesting a more limited capacity for direct protein engagement.
Integrating genomics, bioinformatics, and molecular docking provides an effective strategy for identifying and prioritizing drug repurposing candidates in prostate cancer. Estradiol-benzoate, estradiol-cypionate, and selumetinib emerge as promising candidates, meriting further preclinical and clinical evaluation for advanced prostate cancer therapy.
前列腺癌仍然是一项全球性的普遍健康挑战，晚期前列腺癌的治疗选择有限。迫切需要通过系统整合基因组和生物学数据来确定有效的治疗方法。
我们分析了来自全基因组和全表型关联研究的554个基因中的10911个单核苷酸多态性（SNP），以确定前列腺癌的生物学风险基因。生物信息学分析用于将这些基因映射到关键通路和潜在药物靶点。通过在PC3前列腺癌细胞系中进行连接图谱（CMap）转录组特征分析评估药物重新利用的机会，并进行额外的分子对接研究以评估药物与靶点的相互作用。
我们鉴定出77个与前列腺癌相关的基因。药物重新利用分析揭示了59种靶向13个基因的药物，其中包括11种已批准用于前列腺癌治疗的药物以及22种处于临床或临床前开发阶段的药物。值得注意的是，26种候选药物此前未与前列腺癌相关联。CMap分析将五种候选药物列为优先：苯甲酸雌二醇和环戊丙酸雌二醇（靶向ESR2），其CMap分数最高；达那唑和羟甲烯龙（靶向AR）；以及司美替尼（靶向MAP2K1/MEK），每种药物都显示出调节前列腺癌关键通路的潜力。分子对接分析进一步支持了这些发现，表明苯甲酸雌二醇和环戊丙酸雌二醇对ESR2具有很强的预测结合亲和力，而司美替尼与MAP2K1有强烈的相互作用。相反，达那唑和羟甲烯龙的预测结合较弱，表明其直接与蛋白质结合的能力较为有限。
整合基因组学、生物信息学和分子对接为鉴定前列腺癌药物重新利用候选药物并对其进行优先级排序提供了一种有效策略。苯甲酸雌二醇、环戊丙酸雌二醇和司美替尼成为有前景的候选药物，值得进一步进行晚期前列腺癌治疗的临床前和临床评估。
