article · Molecules
Cancer progression is often driven by abnormal cellular signalling, with the kinases BRAF and VEGFR-2 showing cooperative effects on tumour growth. In an effort to target both enzymes simultaneously, 18 amino-benzothiazole derivatives were designed and synthesised. Biological testing against three cancer cell lines identified four compounds with strong antiproliferative effects. These molecules displayed much lower toxicity towards healthy cells compared to the reference drug sorafenib. Detailed testing of the most promising candidate, compound 4f, revealed that it effectively inhibits both BRAF and VEGFR-2 at levels comparable to sorafenib. Additionally, compound 4f induced cell cycle arrest at the G2-M and S phases. Computational modelling confirmed that compound 4f binds securely within the active sites of both target kinases, showing molecular interactions similar to established inhibitor drugs.
Treating cancer effectively often requires hitting multiple biological targets at once to prevent tumours from growing and developing resistance. By targeting two key cancer-driving enzymes simultaneously, these new chemical compounds show high potency against tumour cells while sparing healthy cells far better than existing therapies. This dual-action approach could contribute to safer and more targeted future cancer treatments.
This research could serve pharmaceutical companies seeking early-stage lead compounds for targeted oncology therapies. The compounds target cancer mechanisms via dual-kinase inhibition and show superior safety profiles relative to sorafenib in laboratory models. However, this work remains at an early discovery stage, having been evaluated only via in vitro cell assays and computer modelling, meaning substantial preclinical testing and optimisation are required before clinical use.
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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-<b>4a</b>, <b>4f</b>, <b>4l</b>, and <b>4r</b>-demonstrated remarkable cytotoxicity, with IC<sub>50</sub> values ranging from 3.58 to 15.36 μM, against three cancer cell lines. Furthermore, these compounds showed IC<sub>50</sub> 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 <b>4f</b> exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC<sub>50</sub> values similar to sorafenib (0.071 and 0.194 μM, respectively). Moreover, compound <b>4f</b> caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where <b>4f</b> 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.
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DOI: 10.3390/molecules29133186
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