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Philadelphia chromosome is characterized by the BCR::ABL fusion gene, which results from this recombination. It transcribes into active tyrosine kinase variants such as P185, P190, P210, and P230, depending on breakpoint chain variations. The fusion protein, encodes tyrosine kinases with varying exons, resulting in uncontrollable ATP-utilizing downstream signaling activities. Targeted therapy with various tyrosine kinase inhibitors (TKIs) is used to combat BCR::ABL fusion kinases and increase the survival rate of patients. However, the incidence of TKI resistance among CML patients is widely noticed around the world. Hence, an elaborate and accurate understanding of the structural interactions between BCR::ABL encoded tyrosine kinases, which are responsible for sensitivity and resistance, is mandatory for hassle-free targeted therapy. This review is intended to cover the reported structural interactions between BCR::ABL variants and TKI ligands in detail to highlight strategies that may be applied in the near future to overcome the resistance and other cross-reactions.<\/jats:p>","DOI":"10.1186\/s43046-025-00263-5","type":"journal-article","created":{"date-parts":[[2025,4,6]],"date-time":"2025-04-06T23:02:35Z","timestamp":1743980555000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Current and future of targeted therapies against BCR::ABL kinases"],"prefix":"10.1186","volume":"37","author":[{"given":"Sridhar","family":"Jayavel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manasvini","family":"Subramanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep Kumar","family":"Kesavan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh","family":"Jayavel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,7]]},"reference":[{"issue":"9","key":"263_CR1","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1002\/ajh.26642","volume":"97","author":"E Jabbour","year":"2022","unstructured":"Jabbour E, Kantarjian H. 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