TY - JOUR
T1 - Pexmetinib
T2 - A novel dual inhibitor of Tie2 and p38 MAPK with efficacy in preclinical models of myelodysplastic syndromes and acute myeloid leukemia
AU - Bachegowda, Lohith
AU - Morrone, Kerry
AU - Winski, Shannon L.
AU - Mantzaris, Ioannis
AU - Bartenstein, Matthias
AU - Ramachandra, Nandini
AU - Giricz, Orsi
AU - Sukrithan, Vineeth
AU - Nwankwo, George
AU - Shahnaz, Samira
AU - Bhagat, Tushar D.
AU - Bhattacharyya, Sanchari
AU - Assal, Amer
AU - Shastri, Aditi
AU - Gordon-Mitchell, Shanisha
AU - Pellagatti, Andrea
AU - Boultwood, Jacqueline
AU - Schinke, Carolina
AU - Yu, Yiting
AU - Guha, Chandan
AU - Rizzi, James
AU - Garrus, Jennifer
AU - Brown, Suzy
AU - Wollenberg, Lance
AU - Hogeland, Grant
AU - Wright, Dale
AU - Munson, Mark
AU - Rodriguez, Mareli
AU - Gross, Stefan
AU - Chantry, David
AU - Zou, Yiyu
AU - Platanias, Leonidas C.
AU - Burgess, Laurence E.
AU - Pradhan, Kith
AU - Steidl, Ulrich
AU - Verma, Amit
N1 - Publisher Copyright:
© 2016 AACR.
PY - 2016/8/15
Y1 - 2016/8/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-15-3062
DO - 10.1158/0008-5472.CAN-15-3062
M3 - Article
C2 - 27287719
AN - SCOPUS:84982085536
SN - 0008-5472
VL - 76
SP - 4841
EP - 4849
JO - Cancer research
JF - Cancer research
IS - 16
ER -
