{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T06:39:31Z","timestamp":1792305571373,"version":"4.4.0"},"reference-count":84,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Resistance to imatinib remains a therapeutic challenge, largely driven by point mutations within the kinase domain of the BCR-ABL, among which the T315I substitution constitutes the most clinically significant barrier. Ponatinib effectively inhibits this mutant form but is limited by dose-dependent cardiovascular toxicity, prompting efforts to develop safer and more selective agents. Recent advances highlight aminopyrimidine-derived scaffolds and their evolution into thienopyrimidines, oxadiazoles, and pyrazines with improved activity against BCR-ABLT315I. Further progress has been achieved with benzothiazole\u2013picolinamide hybrids incorporating a urea-based pharmacophore, which benefit from strategic hinge-region substitutions and phenyl linkers that enhance potency. Parallel research into dual-mechanism inhibitors, including Aurora and p38 kinase modulators, demonstrates additional opportunities for overcoming resistance. Combination strategies, such as vorinostat with ponatinib, provide complementary therapeutic avenues. Natural-product-inspired approaches utilizing fungal metabolites provided structurally diverse scaffolds that could engage sterically constrained mutant kinases. Hybrid molecules derived from approved TKIs, including GNF-7, olverembatinib, and HG-7-85-01, exemplify rational design trends that balance efficacy with improved safety. Molecular modeling continues to deepen understanding of ligand engagement within the T315I-mutated active site, supporting the development of next-generation inhibitors. In this review, we summarized recent progress in the design, optimization, and biological evaluation of small molecules targeting the BCR-ABLT315I mutation.<\/jats:p>","DOI":"10.3390\/molecules31020341","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T14:58:54Z","timestamp":1768834734000},"page":"341","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Advances in Targeting BCR-ABLT315I Mutation with Imatinib Derivatives and Hybrid Anti-Leukemic Molecules"],"prefix":"10.3390","volume":"31","author":[{"given":"Aleksandra","family":"Tuzikiewicz","sequence":"first","affiliation":[{"name":"Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiktoria","family":"Wawrzyniak","sequence":"additional","affiliation":[{"name":"Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9518-4142","authenticated-orcid":false,"given":"Andrzej","family":"Kutner","sequence":"additional","affiliation":[{"name":"Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6781-0329","authenticated-orcid":false,"given":"Teresa","family":"\u017bo\u0142ek","sequence":"additional","affiliation":[{"name":"Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1039\/C8RA10096A","article-title":"Design, synthesis and broad-spectrum Bcr-Abl inhibitory activity of novel thiazolamide-benzamide derivatives","volume":"9","author":"Liu","year":"2019","journal-title":"RSC Adv."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1021\/acs.jcim.1c01554","article-title":"Discovery of Anticancer Hybrid Molecules by Supervised Machine Learning Models and in Vitro Validation in Drug Resistant Chronic Myeloid Leukemia Cells","volume":"62","author":"Melge","year":"2022","journal-title":"J. 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