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

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

  • JCI Insight. 2016 Mar;1(3):e85630. doi: 10.1172/jci.insight.85630.
Katherine A Minson 1,  Catherine C Smith 2,  Deborah DeRyckere 1 3,  Clara Libbrecht 4,  Alisa B Lee-Sherick 4,  Madeline G Huey 1,  Elisabeth A Lasater 2,  Gregory D Kirkpatrick 4,  Michael A Stashko 5,  Weihe Zhang 5,  Craig T Jordan 6,  Dmitri Kireev 5,  Xiaodong Wang 5,  Stephen V Frye 5 7,  H Shelton Earp 7 8,  Neil P Shah 2,  Douglas K Graham 1 3
Affiliations

Affiliations

  • 1 Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA.
  • 2 UCSF, Department of Medicine, San Francisco, California, USA.
  • 3 Winship Cancer Institute, Emory University, Atlanta, GA, USA.
  • 4 University of Colorado, Department of Pediatrics, Aurora, Colorado, USA.
  • 5 University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
  • 6 University of Colorado, Department of Medicine, Aurora, Colorado, USA.
  • 7 UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 8 University of North Carolina at Chapel Hill, Department of Medicine, Chapel Hill, North Carolina, USA.
PMID: 27158668 DOI: 10.1172/jci.insight.85630
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101549
    99.70%, MERTK/FLT3 抑制剂
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