article · Journal of Medicinal Chemistry
A series of coumarin-based thiazole compounds was designed and synthesised to simultaneously inhibit carbonic anhydrase IX and VEGFR-2, two proteins associated with solid tumours. Laboratory evaluations revealed that three specific compounds, labelled 5a, 5d, and 5e, effectively suppressed both enzyme targets. When tested across pancreatic, breast, and prostate cancer cell lines, these three compounds exhibited cytotoxic activity. Detailed mechanistic investigation showed that compound 5e arrests the cell cycle of pancreatic cancer cells in the S stage by activating an apoptotic pathway, marked by increased levels of BAX and caspases 3 and 9, alongside decreased Bcl-2 levels. Computational docking and dynamic simulations confirmed key binding interactions with both target pockets, and the antitumor efficacy of compound 5e was further evaluated in vivo.
Treating solid tumours often requires attacking multiple disease mechanisms simultaneously to improve therapeutic outcomes. Dual-action molecules that suppress both tumor survival factors and vascular growth could provide more effective therapeutic options against aggressive malignancies, including pancreatic, breast, and prostate cancers, where single-target treatments frequently encounter resistance or limited efficacy.
This work identifies early-stage lead compounds that could interest biotechnology and pharmaceutical firms developing solid tumour therapeutics. Because the findings are limited to in vitro assays, computational models, and initial in vivo testing, the molecules remain at an early discovery stage. Significant medicinal chemistry optimisation, toxicology screening, and preclinical pharmacokinetic studies will be required before any clinical translation can occur.
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A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (<b>5a</b>-<b>h</b>, <b>6</b>, and <b>7a</b>-<b>e</b>) 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 <b>5a</b>, <b>5d</b>, and <b>5e</b> can effectively inhibit both targets. <b>5a</b>, <b>5d</b>, and <b>5e</b> cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of <b>5e</b> 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 <i>in vivo</i> efficacy of compound <b>5e</b> as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between <b>5e</b> and CA IX and VEGFR-2 binding pockets.
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DOI: 10.1021/acs.jmedchem.4c00239
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