Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR‑2 as Potential Agents for Solid Tumors: X‑ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

A dual-targeting approach is predicted to yield better
cancer therapy
outcomes. Consequently, a series of coumarin-based thiazoles (5a–h, 6, and 7a–e) were designed and constructed as potential
carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions
of the target compounds were assessed against CA isoforms IX and VEGFR-2.
The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both
targets. 5a, 5d, and 5e cytotoxic
effects were tested on pancreatic, breast, and prostate cancer cells
(PANC1, MCF7, and PC3). Further mechanistic investigation disclosed
the ability of 5e to interrupt the PANC1 cell progression
in the S stage by triggering the apoptotic cascade, as seen by increased
levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover,
the in vivo efficacy of compound 5e as
an antitumor agent was evaluated. Also, molecular docking and dynamics
displayed distinctive interactions between 5e and CA
IX and VEGFR-2 binding pockets.

双靶点策略预计将产生更优的癌症治疗效果。因此，一系列基于香豆素类噻唑（5a–h，6，以及7a–e）被设计并构建，作为潜在的碳酸酐酶（CA）和VEGFR-2抑制剂。针对目标化合物的抑制作用，对CA同工酶IX和VEGFR-2进行了评估。实验结果表明，香豆素类噻唑5a、5d和5e能够有效抑制这两个靶点。5a、5d和5e的细胞毒性作用在胰腺癌、乳腺癌和前列腺癌细胞（PANC1、MCF7和PC3）上进行了测试。进一步机制研究揭示了5e通过触发凋亡级联反应，在S期阻断PANC1细胞进展的能力，表现为caspases 3、9和BAX水平的升高以及Bcl-2的下降。此外，作为抗肿瘤药物，化合物5e的体内疗效也得到了评估。分子对接和动力学分析显示了5e与CA IX和VEGFR-2结合口袋的独特相互作用。