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Ref Type Journal Article
PMID (35499387)
Authors Rice WG, Howell SB, Zhang H, Rastgoo N, Local A, Kurtz SE, Lo P, Bottomly D, Wilmot B, McWeeney SK, Druker BJ, Tyner JW
Title Luxeptinib (CG-806) targets FLT3 and clusters of kinases operative in acute myeloid leukemia.
Journal Molecular cancer therapeutics
Vol
Issue
Date 2022 May 02
URL
Abstract Text 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 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-ITD, FLT3 kinase domain and gatekeeper mutants than against wild type 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, IDH1/2, ASXL1, NPM1, SRSF2, TP53 or RAS, and activity was documented in a xenograft AML model. Luxeptinib administered continuously PO every 12 h at a dose that yielded a mean Cmin plasma concentration of 1.0 {plus minus} 0.3 µM (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 1 trial for patients with AML and myelodysplastic/myeloproliferative neoplasms (MDS/MPN).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins hematologic cancer sensitive CG-806 Preclinical - Cell culture Actionable In a preclinical study, CG-806 inhibited proliferation of a cell line expressing a FLT3 exon 14 insertion (ITD) mutation in culture (PMID: 35499387). 35499387
FLT3 D835Y hematologic cancer sensitive CG-806 Preclinical - Cell culture Actionable In a preclinical study, CG-806 inhibited proliferation of a cell line expressing FLT3 D835Y in culture (PMID: 35499387). 35499387
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive CG-806 Preclinical - Cell culture Actionable In a preclinical study, CG-806 inhibited proliferation of a cell line expressing a FLT3 exon 14 insertion (ITD) mutation and FLT3 D835Y in culture (PMID: 35499387). 35499387
FLT3 exon 14 ins FLT3 F691L hematologic cancer sensitive CG-806 Preclinical - Cell culture Actionable In a preclinical study, CG-806 inhibited proliferation of a cell line expressing a FLT3 exon 14 insertion (ITD) mutation and FLT3 F691L in culture (PMID: 35499387). 35499387
FLT3 exon 14 ins acute myeloid leukemia sensitive CG-806 Preclinical - Cell line xenograft Actionable In a preclinical study, CG-806 inhibited downstream signaling, induced apoptosis, and inhibited proliferation of acute myeloid leukemia cell lines harboring a FLT3 exon 14 insertion (ITD) mutation in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 35499387). 35499387