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We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301\/ON123300), with high potency against CSF1R (IC<jats:sub>50<\/jats:sub>\u2009~\u20090.285\u00a0nM), would have anti-AML effects. We tested this by confirming HX301\u2019s high potency against CSF1R (IC<jats:sub>50<\/jats:sub>\u2009~\u20090.285\u00a0nM), as well as other kinases, <jats:italic>e.g<\/jats:italic>. FLT3 (IC<jats:sub>50<\/jats:sub> of\u2009~\u200919.77\u00a0nM) and CDK6 (0.53\u00a0nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC<jats:sub>50<\/jats:sub> of 72.5\u00a0nM) and a subset of AML lines (IC<jats:sub>50<\/jats:sub>\u2009&lt;\u20091.5\u00a0\u03bcM). In vivo pharmacology modeling of narazaciclib using five AML xenografts resulted in: inhibition of MV4-11 (FLT3-ITD) subcutaneous tumor growth and complete suppression of AM7577-PDX (FLT3-ITD\/CSF1R<jats:sup>med<\/jats:sup>) systemic growth, likely due to the suppression of FLT3-ITD activity; complete suppression of AM8096-PDX (CSF1R<jats:sup>hi<\/jats:sup>\/wild-type FLT3) growth, likely due to the inhibition of CSF1R (\u201ca putative driver\u201d); and nonresponse of both AM5512-PDX and AM7407-PDX (wild-type FLT3\/CSF1R<jats:sup>lo<\/jats:sup>). Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577\/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1R<jats:sup>hi<\/jats:sup> and\/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.<\/jats:p>","DOI":"10.1038\/s41598-024-59650-y","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T14:01:52Z","timestamp":1713535312000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models"],"prefix":"10.1038","volume":"14","author":[{"given":"Tao","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hang","family":"Ke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"An","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Xue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinying","family":"Ning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Hao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingxin","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bing","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengzheng","family":"Bao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kefeng","family":"Gong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi-Xiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,4,19]]},"reference":[{"key":"59650_CR1","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.exphem.2016.09.004","volume":"45","author":"X An","year":"2017","unstructured":"An, X. et al. 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