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Luxeptinib (CG-806) Targets FLT3 and Clusters of Kinases Operative in Acute Myeloid Leukemia.
Rice, William G; Howell, Stephen B; Zhang, Hongying; Rastgoo, Nasrin; Local, Andrea; Kurtz, Stephen E; Lo, Pierrette; Bottomly, Daniel; Wilmot, Beth; McWeeney, Shannon K; Druker, Brian J; Tyner, Jeffrey W.
Afiliación
  • Rice WG; Aptose Biosciences, Inc, San Diego, California.
  • Howell SB; Department of Medicine and the Moores Cancer Center, University of California, San Diego, California.
  • Zhang H; Aptose Biosciences, Inc, San Diego, California.
  • Rastgoo N; Aptose Biosciences, Inc, San Diego, California.
  • Local A; Aptose Biosciences, Inc, San Diego, California.
  • Kurtz SE; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
  • Lo P; Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon.
  • Bottomly D; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
  • Wilmot B; Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon.
  • McWeeney SK; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
  • Druker BJ; Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, Oregon.
  • Tyner JW; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
Mol Cancer Ther ; 21(7): 1125-1135, 2022 07 05.
Article en En | MEDLINE | ID: mdl-35499387
ABSTRACT
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda Límite: Animals / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2022 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda Límite: Animals / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2022 Tipo del documento: Article
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