Pexmetinib: A novel dual inhibitor of Tie2 and p38 MAPK with efficacy in preclinical models of myelodysplastic syndromes and acute myeloid leukemia

Lohith Bachegowda, Kerry Morrone, Shannon L. Winski, Ioannis Mantzaris, Matthias Bartenstein, Nandini Ramachandra, Orsi Giricz, Vineeth Sukrithan, George Nwankwo, Samira Shahnaz, Tushar D. Bhagat, Sanchari Bhattacharyya, Amer Assal, Aditi Shastri, Shanisha Gordon-Mitchell, Andrea Pellagatti, Jacqueline Boultwood, Carolina Schinke, Yiting Yu, Chandan GuhaJames Rizzi, Jennifer Garrus, Suzy Brown, Lance Wollenberg, Grant Hogeland, Dale Wright, Mark Munson, Mareli Rodriguez, Stefan Gross, David Chantry, Yiyu Zou, Leonidas C. Platanias, Laurence E. Burgess, Kith Pradhan, Ulrich Steidl, Amit Verma

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34+ stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML.

Original languageEnglish (US)
Pages (from-to)4841-4849
Number of pages9
JournalCancer research
Volume76
Issue number16
DOIs
StatePublished - Aug 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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