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Acquired drug resistance in mutant Bcr\u2010Abl has enhanced pathogenesis with the use of single therapy agents such as nilotinib. Moreover, allosteric targeting has been identified to consequentially inhibit Bcr\u2010Abl activity, which led to the recent development of <jats:styled-content style=\"fixed-case\">ABL<\/jats:styled-content>\u2010001 (asciminib) that selectively binds the myristoyl pocket. Experimental studies have revealed that the combination of nilotinib and <jats:styled-content style=\"fixed-case\">ABL<\/jats:styled-content>\u2010001 induced a \u2018bent\u2019 conformation in the C\u2010terminal helix of Bcr\u2010Abl; a benchmark of inhibition, thereby exhibiting a greater potency in the treatment of <jats:styled-content style=\"fixed-case\">CML<\/jats:styled-content>, surmounting the setbacks of drug resistance, disease regression and relapse. Therefore, we report the first account of the dynamics and conformational analysis of oncogenic T334I Bcr\u2010Abl by dual targeting. Our findings revealed that unlike in the Bcr\u2010Abl\u2010Nilotinib complex, dual targeting by both inhibitors induced the bent conformation in the C\u2010terminal helix that varied with time. This was coupled with significant alteration in Bcr\u2010Abl stability, flexibility, and compactness and an overall structural re\u2010orientation inwards towards the hydrophobic core, which reduced the solvent\u2010exposed residues indicative of protein folding. This study will facilitate allosteric targeting and the design of more potent allosteric inhibitors for resistive target proteins in cancer.<\/jats:p>","DOI":"10.1002\/cbdv.201700533","type":"journal-article","created":{"date-parts":[[2018,1,12]],"date-time":"2018-01-12T00:22:55Z","timestamp":1515716575000},"source":"Crossref","is-referenced-by-count":14,"title":["Dual Drug Targeting of Mutant Bcr\u2010Abl Induces Inactive Conformation: New Strategy for the Treatment of Chronic Myeloid Leukemia and Overcoming Monotherapy Resistance"],"prefix":"10.1002","volume":"15","author":[{"given":"Ahmed A.","family":"El Rashedy","sequence":"first","affiliation":[{"name":"Molecular Modeling and Drug Design Research Group School of Health Sciences University of KwaZulu\u2010Natal Westville Campus Durban 4001 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fisayo A.","family":"Olotu","sequence":"additional","affiliation":[{"name":"Molecular Modeling and Drug Design Research Group School of Health Sciences University of KwaZulu\u2010Natal Westville Campus Durban 4001 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahmoud E. 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