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 A. Morrone, Shannon L. Winski, Ioannis Mantzaris, Matthias Bartenstein, Nandini Ramachandra, Orsolya 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 Guha & 16 others James 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 G. Steidl, Amit K. Verma

Research output: Contribution to journalArticle

14 Citations (Scopus)

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

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Myelodysplastic Syndromes
p38 Mitogen-Activated Protein Kinases
Acute Myeloid Leukemia
Angiopoietin-1
TIE-2 Receptor
Phosphotransferases
Stem Cells
Hematopoiesis
Hematopoietic Stem Cells
pexmetinib
Bone Marrow
Survival
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Pexmetinib : A novel dual inhibitor of Tie2 and p38 MAPK with efficacy in preclinical models of myelodysplastic syndromes and acute myeloid leukemia. / Bachegowda, Lohith; Morrone, Kerry A.; Winski, Shannon L.; Mantzaris, Ioannis; Bartenstein, Matthias; Ramachandra, Nandini; Giricz, Orsolya; Sukrithan, Vineeth; Nwankwo, George; Shahnaz, Samira; Bhagat, Tushar D.; 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 C.; Burgess, Laurence E.; Pradhan, Kith; Steidl, Ulrich G.; Verma, Amit K.

In: Cancer Research, Vol. 76, No. 16, 15.08.2016, p. 4841-4849.

Research output: Contribution to journalArticle

Bachegowda, L, Morrone, KA, Winski, SL, Mantzaris, I, Bartenstein, M, Ramachandra, N, Giricz, O, Sukrithan, V, Nwankwo, G, Shahnaz, S, Bhagat, TD, Bhattacharyya, S, Assal, A, Shastri, A, Gordon-Mitchell, S, Pellagatti, A, Boultwood, J, Schinke, C, Yu, Y, Guha, C, Rizzi, J, Garrus, J, Brown, S, Wollenberg, L, Hogeland, G, Wright, D, Munson, M, Rodriguez, M, Gross, S, Chantry, D, Zou, Y, Platanias, LC, Burgess, LE, Pradhan, K, Steidl, UG & Verma, AK 2016, 'Pexmetinib: A novel dual inhibitor of Tie2 and p38 MAPK with efficacy in preclinical models of myelodysplastic syndromes and acute myeloid leukemia', Cancer Research, vol. 76, no. 16, pp. 4841-4849. https://doi.org/10.1158/0008-5472.CAN-15-3062
Bachegowda, Lohith ; Morrone, Kerry A. ; Winski, Shannon L. ; Mantzaris, Ioannis ; Bartenstein, Matthias ; Ramachandra, Nandini ; Giricz, Orsolya ; Sukrithan, Vineeth ; Nwankwo, George ; Shahnaz, Samira ; Bhagat, Tushar D. ; 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 C. ; Burgess, Laurence E. ; Pradhan, Kith ; Steidl, Ulrich G. ; Verma, Amit K. / Pexmetinib : A novel dual inhibitor of Tie2 and p38 MAPK with efficacy in preclinical models of myelodysplastic syndromes and acute myeloid leukemia. In: Cancer Research. 2016 ; Vol. 76, No. 16. pp. 4841-4849.
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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.",
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AU - Bachegowda, Lohith

AU - Morrone, Kerry A.

AU - Winski, Shannon L.

AU - Mantzaris, Ioannis

AU - Bartenstein, Matthias

AU - Ramachandra, Nandini

AU - Giricz, Orsolya

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 G.

AU - Verma, Amit K.

PY - 2016/8/15

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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.

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