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The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia
Katherine A. Minson, … , Neil P. Shah, Douglas K. Graham
Katherine A. Minson, … , Neil P. Shah, Douglas K. Graham
Published March 17, 2016
Citation Information: JCI Insight. 2016;1(3):e85630. https://doi.org/10.1172/jci.insight.85630.
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Research Article Oncology

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

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Abstract

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.

Authors

Katherine A. Minson, Catherine C. Smith, Deborah DeRyckere, Clara Libbrecht, Alisa B. Lee-Sherick, Madeline G. Huey, Elisabeth A. Lasater, Gregory D. Kirkpatrick, Michael A. Stashko, Weihe Zhang, Craig T. Jordan, Dmitri Kireev, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Neil P. Shah, Douglas K. Graham

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Figure 1

MRX-2843 is a dual MERTK and FLT3 TKI.

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MRX-2843 is a dual MERTK and FLT3 TKI.
(A) Chemical structure of MRX-284...
(A) Chemical structure of MRX-2843, with an enzymatic IC50 of 1.3 nM for MERTK and 0.64 nM for FLT3 (B) Chemical structure of UNC2369, which lacks significant activity against MERTK (enzymatic IC50 of 490 nM) or FLT3 (enzymatic IC50 of 360 nM) and was used as a negative control in these studies. FLT3, FMS-like tyrosine kinase 3; TKI, tyrosine kinase inhibitor.
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