Pexmetinib: a novel dual inhibitor of Tie-2 and p38 MAPK with efficacy in preclinical models of myelodysplastic syndromes and acute myeloid leukemia

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...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2016-06, Vol.76 (16), p.4841-4849
Main Authors: Bachegowda, Lohith, Morrone, Kerry, Winski, Shannon L., Mantzaris, Ioannis, Bartenstein, Matthias, Ramachandra, Nandini, Giricz, Orsi, Sukrithan, Vineeth, Nwankwo, George, Shahnaz, Samira, Bhagat, Tushar, Bhattacharyya, Sanchari, Assal, Amer, Shastri, Aditi, Gordon-Mitchell, Shanisha, Pellagatti, Andrea, Boultwood, Jacqueline, Schinke, Carolina, Yu, Yiting, Guha, Chandan, Rizzi, James, Garrus, Jennifer, Brown, Suzy, Wollenberg, Lance, Hogeland, Grant, Wright, Dale, Munson, Mark, Rodriguez, Mareli, Gross, Stefan, Chantry, David, Zou, Yiyu, Platanias, Leonidas, Burgess, Laurence E., Pradhan, Kith, Steidl, Ulrich, Verma, Amit
Format: Article
Language:English
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Summary: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 pro-inflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases and abrogated the effects of TNF-alpha 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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-15-3062