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- Title
Identification of Benzothiazoles Bearing 1,3,4-Thiadiazole as Antiproliferative Hybrids Targeting VEGFR-2 and BRAF Kinase: Design, Synthesis, BIO Evaluation and In Silico Study.
- Authors
Ewes, Wafaa A.; Tawfik, Samar S.; Almatary, Aya M.; Bhat, Mashooq Ahmad; El-Shafey, Hamed W.; Mohamed, Ahmed A. B.; Haikal, Abdullah; El-Magd, Mohammed A.; Elgazar, Abdullah A.; Balaha, Marwa; Hamdi, Abdelrahman
- Abstract
Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds—4a, 4f, 4l, and 4r—demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 µM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77–66.22 µM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 µM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib.
- Publication
Molecules, 2024, Vol 29, Issue 13, p1
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules29133186