Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia

  • Cancer Res. 2016 Aug 15;76(16):4841-4849. doi: 10.1158/0008-5472.CAN-15-3062.
Lohith Bachegowda   #  1 ,  Kerry Morrone   #  1 ,  Shannon L Winski   #  2 ,  Ioannis Mantzaris   #  1 ,  Matthias Bartenstein  1 ,  Nandini Ramachandra  1 ,  Orsi Giricz  1 ,  Vineeth Sukrithan  1 ,  George Nwankwo  1 ,  Samira Shahnaz  1 ,  Tushar Bhagat  1 ,  Sanchari Bhattacharyya  1 ,  Amer Assal  1 ,  Aditi Shastri  1 ,  Shanisha Gordon-Mitchell  1 ,  Andrea Pellagatti  3 ,  Jacqueline Boultwood  3 ,  Carolina Schinke  1 ,  Yiting Yu  1 ,  Chandan Guha  1 ,  James Rizzi  2 ,  Jennifer Garrus  2 ,  Suzy Brown  2 ,  Lance Wollenberg  2 ,  Grant Hogeland  2 ,  Dale Wright  2 ,  Mark Munson  2 ,  Mareli Rodriguez  2 ,  Stefan Gross  2 ,  David Chantry  2 ,  Yiyu Zou  1 ,  Leonidas Platanias  4 ,  Laurence E Burgess  2 ,  Kith Pradhan  1 ,  Ulrich Steidl  1 ,  Amit Verma  1
Affiliations
  • 1. Albert Einstein College of Medicine, Bronx , NY.
  • 2. Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
  • 3. LLR Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, and NIHR Biomedical Research Centre, Oxford, UK.
  • 4. Northwestern University, Chicago, IL.
  • # Contributed equally.
PMID: 27287719 DOI: 10.1158/0008-5472.CAN-15-3062
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. Cancer Res; 76(16); 4841-9. ©2016 AACR.

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