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Despite the therapeutic success of current VEGFR\u20102 inhibitors, their clinical utility is often constrained by acquired resistance, off\u2010target toxicities, and suboptimal selectivity. The 1,3,4\u2010thiadiazole (TDA) scaffold has emerged as a privileged moiety in cancer drug discovery due to its mesoionic character, structural diversity, and molecular pharmacology. Notably, the \u2500N\u2500N\u2550C\u2500S motif and sulfur atom of TDA significantly contribute to VEGFR\u20102 binding through key molecular interactions. This work provides a comprehensive overview of the role of VEGFR\u20102 in cancer biology, the chemistry of 1,3,4\u2010TDA, and the mechanistic basis of VEGFR\u20102 inhibition. A systematic analysis of different publications from the last decade led to the extraction and evaluation of 151 TDA\u2010based VEGFR\u20102 inhibitors. Chemical space, structure\u2013activity relationship (SAR), substitution patterns, selectivity, toxicity, and essential binding interactions (ATP or allosteric site) with VEGFR\u20102 were critically examined. The review underscores the potential of 1,3,4\u2010TDA derivatives as promising scaffolds for selective and efficacious VEGFR\u20102 inhibition, offering strategic guidance for the rational design of next\u2010generation VEGFR\u20102 inhibitors with improved efficiency, selectivity, and reduced toxicity for anticancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/cbdv.202501361","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T19:05:46Z","timestamp":1756235146000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["1,3,4\u2010Thiadiazole Derivatives as VEGFR\u20102 Inhibitors and Its Molecular Insight for Cancer Therapy"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0707-0396","authenticated-orcid":false,"given":"Pragya","family":"Gawande","sequence":"first","affiliation":[{"name":"Laboratory of Drug Discovery and Ecotoxicology, 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