Department of Pharmaceutical Sciences, School of Biomedical and Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, Uttar Pradesh, India.
Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharaj, Saudi Arabia.
Chem Biol Drug Des. 2024 May;103(5):e14531. doi: 10.1111/cbdd.14531.
Inhibition of prolylhydroxylase-2 (PHD-2) in both normoxic and hypoxic cells is a critical component of solid tumours. The present study aimed to identify small molecules with PHD-2 activation potential. Virtually screening 4342 chemical compounds for structural similarity to R59949 and docking with PHD-2. To find the best drug candidate, hits were assessed for drug likeliness, antihypoxic and antineoplastic potential. The selected drug candidate's PHD-2 activation, cytotoxic and apoptotic potentials were assessed using 2-oxoglutarate, MTT, AO/EtBr and JC-1 staining. The drug candidate was also tested for its in-vivo chemopreventive efficacy against DMBA-induced mammary gland cancer alone and in combination with Tirapazamine (TPZ). Virtual screening and 2-oxoglutarate assay showed BBAP-6 as lead compound. BBAP-6 exhibited cytotoxic and apoptotic activity against ER+ MCF-7. In carmine staining and histology, BBAP-6 alone or in combination with TPZ restored normal surface morphology of the mammary gland after DMBA produced malignant alterations. Immunoblotting revealed that BBAP-6 reduced NF-κB expression, activated PHD-2 and induced intrinsic apoptotic pathway. Serum metabolomics conducted with 1H NMR confirmed that BBAP-6 prevented HIF-1α and NF-κB-induced metabolic changes in DMBA mammary gland cancer model. In a nutshell, it can be concluded that BBAP-6 activates PHD-2 and exhibits anticancer potential.
在常氧和缺氧细胞中抑制脯氨酰羟化酶-2（PHD-2）是实体瘤的关键组成部分。本研究旨在鉴定具有 PHD-2 激活潜力的小分子。虚拟筛选 4342 种化学化合物，寻找与 R59949 结构相似的化合物，并与 PHD-2 对接。为了找到最佳的候选药物，对候选药物进行了药物相似性、抗缺氧和抗肿瘤潜力评估。使用 2-氧戊二酸、MTT、AO/EtBr 和 JC-1 染色评估选定候选药物的 PHD-2 激活、细胞毒性和细胞凋亡潜力。还测试了候选药物对 DMBA 诱导的乳腺癌的体内化学预防效果，以及与 Tirapazamine（TPZ）联合使用的效果。虚拟筛选和 2-氧戊二酸测定显示 BBAP-6 是先导化合物。BBAP-6 对 ER+ MCF-7 具有细胞毒性和促凋亡作用。在胭脂红染色和组织学中，BBAP-6 单独或与 TPZ 联合使用可在 DMBA 产生恶性改变后恢复乳腺的正常表面形态。免疫印迹显示 BBAP-6 降低了 NF-κB 的表达，激活了 PHD-2 并诱导了内在凋亡途径。用 1H NMR 进行的血清代谢组学证实，BBAP-6 可预防 HIF-1α 和 NF-κB 诱导的 DMBA 乳腺癌模型中的代谢变化。简而言之，可以得出结论，BBAP-6 激活了 PHD-2 并具有抗癌潜力。
