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

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posted on 2024-04-20, 19:04 authored by Salma M. Hefny, Tarek F. El-Moselhy, Nabaweya El-Din, Simone Giovannuzzi, Thamer Bin Traiki, Mansoor-Ali Vaali-Mohammed, Ahmed M. El-Dessouki, Koki Yamaguchi, Masaharu Sugiura, Moataz A. Shaldam, Claudiu T. Supuran, Maha-Hamadien Abdulla, Wagdy M. Eldehna, Haytham O. Tawfik

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.