Pexmetinib: A Novel Dual Inhibitor of Tie2 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 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.
Albert Einstein College of Medicine, Bronx , NY.
Lohith
L
Bachegowda
Albert Einstein College of Medicine, Bronx , NY.
Kerry
K
Morrone
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
Shannon L
SL
Winski
Albert Einstein College of Medicine, Bronx , NY.
Ioannis
I
Mantzaris
Albert Einstein College of Medicine, Bronx , NY.
Matthias
M
Bartenstein
Albert Einstein College of Medicine, Bronx , NY.
Nandini
N
Ramachandra
Albert Einstein College of Medicine, Bronx , NY.
Orsi
O
Giricz
Albert Einstein College of Medicine, Bronx , NY.
Vineeth
V
Sukrithan
Albert Einstein College of Medicine, Bronx , NY.
George
G
Nwankwo
Albert Einstein College of Medicine, Bronx , NY.
Samira
S
Shahnaz
Albert Einstein College of Medicine, Bronx , NY.
Tushar
T
Bhagat
Albert Einstein College of Medicine, Bronx , NY.
Sanchari
S
Bhattacharyya
Albert Einstein College of Medicine, Bronx , NY.
Amer
A
Assal
Albert Einstein College of Medicine, Bronx , NY.
Aditi
A
Shastri
Albert Einstein College of Medicine, Bronx , NY.
Shanisha
S
Gordon-Mitchell
LLR Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, and NIHR Biomedical Research Centre, Oxford, UK.
Andrea
A
Pellagatti
LLR Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, and NIHR Biomedical Research Centre, Oxford, UK.
Jacqueline
J
Boultwood
Albert Einstein College of Medicine, Bronx , NY.
Carolina
C
Schinke
Albert Einstein College of Medicine, Bronx , NY.
Yiting
Y
Yu
Albert Einstein College of Medicine, Bronx , NY.
Chandan
C
Guha
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
James
J
Rizzi
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
Jennifer
J
Garrus
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
Suzy
S
Brown
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
Lance
L
Wollenberg
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
Grant
G
Hogeland
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
Dale
D
Wright
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
Mark
M
Munson
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
Mareli
M
Rodriguez
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
Stefan
S
Gross
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
David
D
Chantry
Albert Einstein College of Medicine, Bronx , NY.
Yiyu
Y
Zou
Northwestern University, Chicago, IL.
Leonidas
L
Platanias
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
Laurence E
LE
Burgess
Albert Einstein College of Medicine, Bronx , NY.
Kith
K
Pradhan
Albert Einstein College of Medicine, Bronx , NY.
Ulrich
U
Steidl
Albert Einstein College of Medicine, Bronx , NY.
Amit
A
Verma
D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D055785:Gene Knockdown Techniques; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008297:Male; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000473:pathology*; D016016:Proportional Hazards Models; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D000970:Antineoplastic Agents; D007191:Indazoles; C000602876:pexmetinib; D014508:Urea; D042787:Receptor, TIE-2; D048051:p38 Mitogen-Activated Protein Kinases