Reference Detail

Ref Type

Journal Article

PMID

(27158668)

Authors

Minson KA, Smith CC, DeRyckere D, Libbrecht C, Lee-Sherick AB, Huey MG, Lasater EA, Kirkpatrick GD, Stashko MA, Zhang W, Jordan CT, Kireev D, Wang X, Frye SV, Earp HS, Shah NP, Graham DK

Title

The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCI insight	1	3	2016 Mar	e85630	JCI Insight

URL

Abstract Text

FMS-like tyrosine kinase 3-targeted (FLT3-targeted) therapies have shown initial promise for the treatment of acute myeloid leukemia (AML) expressing FLT3-activating mutations; however, resistance emerges rapidly. Furthermore, limited options exist for the treatment of FLT3-independent AML, demonstrating the need for novel therapies that reduce toxicity and improve survival. MERTK receptor tyrosine kinase is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis. Here, we describe MRX-2843, a type 1 small-molecule tyrosine kinase inhibitor that abrogates activation of both MERTK and FLT3 and their downstream effectors. MRX-2843 treatment induces apoptosis and inhibits colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD, with a wide therapeutic window compared with that of normal human cord blood cells. In murine orthotopic xenograft models, once-daily oral therapy prolonged survival 2- to 3-fold over that of vehicle-treated controls. Additionally, MRX-2843 retained activity against quizartinib-resistant FLT3-ITD-mutant proteins with clinically relevant alterations at the D835 or F691 loci and prolonged survival in xenograft models of quizartinib-resistant AML. Together, these observations validate MRX-2843 as a translational agent and support its clinical development for the treatment of AML.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
MRX-2843	MRX-2843	11	2

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
MRX-2843		MRX2843\|MRX 2843	FLT3 Inhibitor 69 MERTK Inhibitor 13	MRX-2843 inhibits MERTK and FLT3, potentially resulting in increased tumor cell apoptosis and enhanced antitumor immune response (PMID: 27158668, PMID: 39322710).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	MRX-2843	Preclinical - Cell line xenograft	Actionable	In a preclinical study, MRX-2843 inhibited Flt3 activation, resulted in growth inhibition in acute myeloid leukemia cell lines harboring FLT3 internal tandem duplication (ITD) in culture and in cell line xenograft models, and prolonged survival in patient-derived xenograft models (PMID: 27158668).	27158668
FLT3 exon 14 ins FLT3 D835Y	acute myeloid leukemia	sensitive	MRX-2843	Preclinical - Cell line xenograft	Actionable	In a preclinical study, MRX-2843 inhibited Flt3 signaling, resulted in growth inhibition in Quizartinib (AC220)-resistant acute myeloid leukemia cells harboring FLT3 internal tandem duplication (ITD) and D835Y in culture, and prolonged survival in cell line xenograft models (PMID: 27158668).	27158668
FLT3 exon 14 ins FLT3 F691L	acute myeloid leukemia	sensitive	MRX-2843	Preclinical - Cell line xenograft	Actionable	In a preclinical study, MRX-2843 inhibited Flt3 signaling, resulted in growth inhibition in Quizartinib (AC220)-resistant acute myeloid leukemia cells harboring FLT3 internal tandem duplication (ITD) and F691L in culture, and prolonged survival in cell line xenograft models (PMID: 27158668).	27158668
FLT3 D835V	Advanced Solid Tumor	sensitive	MRX-2843	Preclinical - Cell culture	Actionable	In a preclinical study, MRX-2843 inhibited Flt3 signaling, resulted in growth inhibition in Quizartinib (AC220)-resistant transformed cells over expressing FLT3 D835V in culture (PMID: 27158668).	27158668
FLT3 D835Y	Advanced Solid Tumor	sensitive	MRX-2843	Preclinical - Cell culture	Actionable	In a preclinical study, MRX-2843 inhibited Flt3 signaling, resulted in growth inhibition in Quizartinib (AC220)-resistant transformed cells over expressing FLT3 D835Y in culture (PMID: 27158668).	27158668
FLT3 exon 14 ins FLT3 D835F	Advanced Solid Tumor	sensitive	MRX-2843	Preclinical - Cell culture	Actionable	In a preclinical study, MRX-2843 inhibited Flt3 signaling, resulted in growth inhibition in Quizartinib (AC220)-resistant transformed cells over expressing both FLT3 internal tandem duplication (ITD) and D835F in culture (PMID: 27158668).	27158668
FLT3 exon 14 ins FLT3 D835V	Advanced Solid Tumor	sensitive	MRX-2843	Preclinical - Cell culture	Actionable	In a preclinical study, MRX-2843 inhibited Flt3 signaling, resulted in growth inhibition in Quizartinib (AC220)-resistant transformed cells over expressing both FLT3 internal tandem duplication (ITD) and D835V in culture (PMID: 27158668).	27158668
FLT3 exon 14 ins FLT3 D835Y	Advanced Solid Tumor	sensitive	MRX-2843	Preclinical - Cell culture	Actionable	In a preclinical study, MRX-2843 inhibited Flt3 signaling, resulted in growth inhibition in Quizartinib (AC220)-resistant transformed cells over expressing both FLT3 internal tandem duplication (ITD) and D835Y in culture (PMID: 27158668).	27158668
FLT3 exon 14 ins FLT3 F691L	Advanced Solid Tumor	sensitive	MRX-2843	Preclinical - Cell culture	Actionable	In a preclinical study, MRX-2843 inhibited Flt3 signaling, resulted in growth inhibition in Quizartinib (AC220)-resistant transformed cells over expressing both FLT3 internal tandem duplication (ITD) and F691L in culture (PMID: 27158668).	27158668
FLT3 exon 14 ins FLT3 Y842C	Advanced Solid Tumor	sensitive	MRX-2843	Preclinical - Cell culture	Actionable	In a preclinical study, MRX-2843 inhibited Flt3 signaling, resulted in growth inhibition in Quizartinib (AC220)-resistant transformed cells over expressing both FLT3 internal tandem duplication (ITD) and Y842C in culture (PMID: 27158668).	27158668
FLT3 exon 14 ins FLT3 Y842H	Advanced Solid Tumor	sensitive	MRX-2843	Preclinical - Cell culture	Actionable	In a preclinical study, MRX-2843 inhibited Flt3 signaling, resulted in growth inhibition in Quizartinib (AC220)-resistant transformed cells over expressing both FLT3 internal tandem duplication (ITD) and Y842H in culture (PMID: 27158668).	27158668

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