Eldehna Wagdy M, Tawfik Haytham O, Nafie Mohamed S, Al Kamaly Omkulthom, El-Hamaky Anwar A, El Hassab Mahmoud A, Elsayed Zainab M, Elnaggar Yosra S R, Al-Karmalawy Ahmed A, di Giacomo Viviana, Balaha Marwa
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
Bioorg Chem. 2025 Jun 15;160:108494. doi: 10.1016/j.bioorg.2025.108494. Epub 2025 Apr 21.
Poly (ADP-ribose) polymerase (PARP) inhibitors have been authorized for the treatment of breast cancer (BC) and prostate cancer (PC). Recent studies suggest that inhibiting angiogenesis through the vascular endothelial growth factor receptor (VEGFR) enhances cellular sensitivity to PARP inhibitors. This study presents the design, synthesis and full characterization of dual VEGFR-2 and PARP-1 inhibitors obtained by conjugating a PARP-1 inhibitor with VEGFR-2 inhibitor fragments (indole, benzofuran, and piperazine). Four compounds exhibited significant inhibitory activities against human prostate cancer cell lines (PC3) and breast cancer cell lines (MCF7) at 48 h. These compounds were identified as dual VEGFR-2 and PARP-1 inhibitors with low or sub-micromolar ranges, especially 12f, with IC values of 0.43 μM and 1.10 μM, respectively. Moreover, the potent compound 12f markedly decreased scratch wound closure and colony formation. Moreover, compound 12f significantly induced apoptosis in PC3 cells and arrested cells at the S phase. The dual inhibition of VEGFR-2 and PARP-1 protein kinase was further validated using western blotting. Applying molecular docking and dynamics determined the target compound's binding mechanism.
聚（ADP - 核糖）聚合酶（PARP）抑制剂已被批准用于治疗乳腺癌（BC）和前列腺癌（PC）。最近的研究表明，通过血管内皮生长因子受体（VEGFR）抑制血管生成可增强细胞对PARP抑制剂的敏感性。本研究介绍了通过将PARP - 1抑制剂与VEGFR - 2抑制剂片段（吲哚、苯并呋喃和哌嗪）偶联而获得的双VEGFR - 2和PARP - 1抑制剂的设计、合成及全面表征。四种化合物在48小时时对人前列腺癌细胞系（PC3）和乳腺癌细胞系（MCF7）表现出显著的抑制活性。这些化合物被鉴定为低或亚微摩尔范围的双VEGFR - 2和PARP - 1抑制剂，尤其是12f，其IC值分别为0.43μM和1.10μM。此外，强效化合物12f显著降低划痕伤口闭合和集落形成。此外，化合物12f显著诱导PC3细胞凋亡并使细胞停滞在S期。使用蛋白质印迹法进一步验证了VEGFR - 2和PARP - 1蛋白激酶的双重抑制作用。应用分子对接和动力学确定了目标化合物的结合机制。
