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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
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MRX-2843 MRX-2843 11 2
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).
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 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 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 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
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 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 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 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 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