激酶
髓系白血病
Fms样酪氨酸激酶3
白血病
癌症研究
药理学
体内
髓样
医学
化学
生物
内科学
生物化学
突变
生物技术
基因
作者
William G. Rice,Stephen B. Howell,Hongying Zhang,Nasrin Rastgoo,Andrea Local,Stephen E. Kurtz,Pierrette Lo,Daniel Bottomly,Beth Wilmot,Shannon K. McWeeney,Brian J. Druker,Jeffrey W. Tyner
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2022-05-02
卷期号:21 (7): 1125-1135
被引量:3
标识
DOI:10.1158/1535-7163.mct-21-0832
摘要
Luxeptinib (CG-806) simultaneously targets FLT3 and select other kinase pathways operative in myeloid malignancies. We investigated the range of kinases it inhibits, its cytotoxicity landscape ex vivo with acute myeloid leukemia (AML) patient samples, and its efficacy in xenograft models. Luxeptinib inhibits wild-type (WT) and many of the clinically relevant mutant forms of FLT3 at low nanomolar concentrations. It is a more potent inhibitor of the activity of FLT3-internal tandem duplication, FLT3 kinase domain and gatekeeper mutants than against WT FLT3. Broad kinase screens disclosed that it also inhibits other kinases that can drive oncogenic signaling and rescue pathways, but spares kinases known to be associated with clinical toxicity. In vitro profiling of luxeptinib against 186 AML fresh patient samples demonstrated greater potency relative to other FLT3 inhibitors, including cases with mutations in FLT3, isocitrate dehydrogenase-1/2, ASXL1, NPM1, SRSF2, TP53, or RAS, and activity was documented in a xenograft AML model. Luxeptinib administered continuously orally every 12 hours at a dose that yielded a mean Cmin plasma concentration of 1.0 ± 0.3 μmol/L (SEM) demonstrated strong antitumor activity but no myelosuppression or evidence of tissue damage in mice or dogs in acute toxicology studies. On the basis of these studies, luxeptinib was advanced into a phase I trial for patients with AML and myelodysplastic/myeloproliferative neoplasms.
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