{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T23:03:32Z","timestamp":1794265412284,"version":"4.9.0"},"reference-count":23,"publisher":"American Society of Hematology","issue":"6","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,8,8]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Secondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia. The first 5 approved BCR::ABL1 TKIs target the adenosine triphosphate (ATP)\u2013binding pocket. Mutations confer resistance to these ATP-competitive TKIs and those approved for other malignancies by decreasing TKI affinity and\/or increasing ATP affinity. Asciminib, the first highly active allosteric TKI approved for any malignancy, targets an allosteric regulatory pocket in the BCR::ABL1 kinase C-lobe. As a non\u2013ATP-competitive inhibitor, the activity of asciminib is predicted to be impervious to increases in ATP affinity. Here, we report several known mutations that confer resistance to ATP-competitive TKIs in the BCR::ABL1 kinase N-lobe that are distant from the asciminib binding pocket yet unexpectedly confer in\u00a0vitro resistance to asciminib. Among these is BCR::ABL1 M244V, which confers clinical resistance even to escalated asciminib doses. We demonstrate that BCR::ABL1 M244V does not impair asciminib binding, thereby invoking a novel mechanism of resistance. Molecular dynamic simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the \u03b1-C helix as a mechanism of resistance. These N-lobe mutations may compromise the clinical activity of ongoing combination studies of asciminib with ATP-competitive TKIs.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023022538","type":"journal-article","created":{"date-parts":[[2024,4,21]],"date-time":"2024-04-21T19:00:11Z","timestamp":1713726011000},"page":"639-645","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":42,"title":["<i>BCR<\/i>::<i>ABL1<\/i> kinase N-lobe mutants confer moderate to high degrees of resistance to asciminib"],"prefix":"10.1182","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0033-2987","authenticated-orcid":false,"given":"Ariel","family":"Leyte-Vidal","sequence":"first","affiliation":[{"name":"1Division of Hematology\/Oncology, Department of Medicine, University of California, San Francisco, CA"},{"name":"2Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2441-385X","authenticated-orcid":false,"given":"Diego","family":"Garrido Ruiz","sequence":"additional","affiliation":[{"name":"3Department of Pharmaceutical Chemistry, University of California, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"RosaAnna","family":"DeFilippis","sequence":"additional","affiliation":[{"name":"1Division of Hematology\/Oncology, Department of Medicine, University of California, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6133-4612","authenticated-orcid":false,"given":"Inga B.","family":"Leske","sequence":"additional","affiliation":[{"name":"4Institute for Physiological Chemistry, Philipps University of Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5379-7461","authenticated-orcid":false,"given":"Delphine","family":"Rea","sequence":"additional","affiliation":[{"name":"5Adult Hematology Department, H\u00f4pital Saint-Louis, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Phan","sequence":"additional","affiliation":[{"name":"1Division of Hematology\/Oncology, Department of Medicine, University of California, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0897-3144","authenticated-orcid":false,"given":"Kaeli B.","family":"Miller","sequence":"additional","affiliation":[{"name":"1Division of Hematology\/Oncology, Department of Medicine, University of California, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifei","family":"Hu","sequence":"additional","affiliation":[{"name":"1Division of Hematology\/Oncology, Department of Medicine, University of California, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5392-2506","authenticated-orcid":false,"given":"Anjeli","family":"Mase","sequence":"additional","affiliation":[{"name":"1Division of Hematology\/Oncology, Department of Medicine, University of California, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibing","family":"Shan","sequence":"additional","affiliation":[{"name":"6Antidote Health Foundation for Cure of Cancer, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8569-8169","authenticated-orcid":false,"given":"Oliver","family":"Hantschel","sequence":"additional","affiliation":[{"name":"4Institute for Physiological Chemistry, Philipps University of Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6262-655X","authenticated-orcid":false,"given":"Matthew P.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"3Department of Pharmaceutical Chemistry, University of California, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4398-3388","authenticated-orcid":false,"given":"Neil P.","family":"Shah","sequence":"additional","affiliation":[{"name":"1Division of Hematology\/Oncology, Department of Medicine, University of California, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"10","key":"2024080815203536000_bib1","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1056\/NEJMoa1609324","article-title":"Long-term outcomes of imatinib treatment for chronic myeloid 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