Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	21	7	2022 Jul 05	1125-1135	Mol Cancer Ther

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 (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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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 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
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 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