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

被引：42

作者：

Bachegowda, Lohith ^{[1
]}

Morrone, Kerry ^{[1
]}

Winski, Shannon L.

Mantzaris, Ioannis ^{[1
]}

Bartenstein, Matthias ^{[1
]}

Ramachandra, Nandini ^{[1
]}

Giricz, Orsi ^{[1
]}

Sukrithan, Vineeth ^{[1
]}

Nwankwo, George ^{[1
]}

Shahnaz, Samira ^{[1
]}

Bhagat, Tushar D. ^{[1
]}

Bhattacharyya, Sanchari ^{[1
]}

Assal, Amer ^{[1
]}

Shastri, Aditi ^{[1
]}

Gordon-Mitchell, Shanisha ^{[1
]}

Pellagatti, Andrea ^{[3
]}

Boultwood, Jacqueline ^{[3
]}

Schinke, Carolina ^{[1
]}

Yu, Yiting ^{[1
]}

Guha, Chandan ^{[1
]}

Rizzi, James ^{[2
]}

Garrus, Jennifer ^{[2
]}

Brown, Suzy ^{[2
]}

Wollenberg, Lance ^{[2
]}

Hogeland, Grant ^{[2
]}

Wright, Dale ^{[2
]}

Munson, Mark ^{[2
]}

Rodriguez, Mareli ^{[2
]}

Gross, Stefan ^{[2
]}

Chantry, David ^{[2
]}

Zou, Yiyu ^{[1
]}

Platanias, Leonidas C. ^{[4
]}

Burgess, Laurence E. ^{[2
]}

Pradhan, Kith ^{[1
]}

Steidl, Ulrich ^{[1
]}

Verma, Amit ^{[1
]}

机构：

[1] Albert Einstein Coll Med, 1300 Morris Pk Ave, Bronx, NY 10461 USA

[2] Array BioPharma Inc, Boulder, CO USA

[3] John Radcliffe Hosp, NDCLS, LLR Mol Haematol Unit, Oxford, England

[4] Northwestern Univ, Chicago, IL 60611 USA

来源：

CANCER RESEARCH | 2016年 / 76卷 / 16期

关键词：

PROTEIN-KINASE PATHWAY; STEM; ACTIVATION; HEMATOPOIESIS; MORTALITY; CELLS; BETA;

D O I：

10.1158/0008-5472.CAN-15-3062

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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 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. (C) 2016 AACR.

引用

页码：4841 / 4849

页数：9

共 19 条

[1]

Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche [J].

Arai, F ;

Hirao, A ;

Ohmura, M ;

Sato, H ;

Matsuoka, S ;

Takubo, K ;

Ito, K ;

Koh, GY ;

Suda, T .

CELL, 2004, 118 (02) :149-161

[2]

Signal transduction inhibitors in treatment of myelodysplastic syndromes [J].

Bachegowda, Lohith ;

Gligich, Oleg ;

Mantzaris, Ionnis ;

Schinke, Carolina ;

Wyville, Dale ;

Carrillo, Tatiana ;

Braunschweig, Ira ;

Steidl, Ulrich ;

Verma, Amit .

JOURNAL OF HEMATOLOGY & ONCOLOGY, 2013, 6

[3]

Clonal Evolution of Preleukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia [J].

Jan, Max ;

Snyder, Thomas M. ;

Corces-Zimmerman, M. Ryan ;

Vyas, Paresh ;

Weissman, Irving L. ;

Quake, Stephen R. ;

Majeti, Ravindra .

SCIENCE TRANSLATIONAL MEDICINE, 2012, 4 (149)

[4]

Multiplicative interaction between mean corpuscular volume and red cell distribution width in predicting mortality of elderly patients with and without anemia [J].

Lam, Anthony P. ;

Gundabolu, Krishna ;

Sridharan, Ashwin ;

Jain, Rishi ;

Msaouel, Pavlos ;

Chrysofakis, Grigorios ;

Yu, Yiting ;

Friedman, Ellen ;

Price, Elizabeth ;

Schrier, Stanley ;

Verma, Amit K. .

AMERICAN JOURNAL OF HEMATOLOGY, 2013, 88 (11) :E245-E249

[5]

NUP98 gene fusions in hematologic malignancies [J].

Lam, DH ;

Aplan, PD .

LEUKEMIA, 2001, 15 (11) :1689-1695

[6]

Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia [J].

Ley, Timothy J. ;

Miller, Christopher ;

Ding, Li ;

Raphael, Benjamin J. ;

Mungall, Andrew J. ;

Robertson, A. Gordon ;

Hoadley, Katherine ;

Triche, Timothy J., Jr. ;

Laird, Peter W. ;

Baty, Jack D. ;

Fulton, Lucinda L. ;

Fulton, Robert ;

Heath, Sharon E. ;

Kalicki-Veizer, Joelle ;

Kandoth, Cyriac ;

Klco, Jeffery M. ;

Koboldt, Daniel C. ;

Kanchi, Krishna-Latha ;

Kulkarni, Shashikant ;

Lamprecht, Tamara L. ;

Larson, David E. ;

Lin, Ling ;

Lu, Charles ;

McLellan, Michael D. ;

McMichael, Joshua F. ;

Payton, Jacqueline ;

Schmidt, Heather ;

Spencer, David H. ;

Tomasson, Michael H. ;

Wallis, John W. ;

Wartman, Lukas D. ;

Watson, Mark A. ;

Welch, John ;

Wendl, Michael C. ;

Ally, Adrian ;

Balasundaram, Miruna ;

Birol, Inanc ;

Butterfield, Yaron ;

Chiu, Readman ;

Chu, Andy ;

Chuah, Eric ;

Chun, Hye-Jung ;

Corbett, Richard ;

Dhalla, Noreen ;

Guin, Ranabir ;

He, An ;

Hirst, Carrie ;

Hirst, Martin ;

Holt, Robert A. ;

Jones, Steven .

NEW ENGLAND JOURNAL OF MEDICINE, 2013, 368 (22) :2059-2074

[7]

DNMT3A Mutations in Acute Myeloid Leukemia. [J].

Ley, Timothy J. ;

Ding, Li ;

Walter, Matthew J. ;

McLellan, Michael D. ;

Lamprecht, Tamara ;

Larson, David E. ;

Kandoth, Cyriac ;

Payton, Jacqueline E. ;

Baty, Jack ;

Welch, John ;

Harris, Christopher C. ;

Lichti, Cheryl F. ;

Townsend, R. Reid ;

Fulton, Robert S. ;

Dooling, David J. ;

Koboldt, Daniel C. ;

Schmidt, Heather ;

Zhang, Qunyuan ;

Osborne, John R. ;

Lin, Ling ;

O'Laughlin, Michelle ;

McMichael, Joshua F. ;

Delehaunty, Kim D. ;

McGrath, Sean D. ;

Fulton, Lucinda A. ;

Magrini, Vincent J. ;

Vickery, Tammi L. ;

Hundal, Jasreet ;

Cook, Lisa L. ;

Conyers, Joshua J. ;

Swift, Gary W. ;

Reed, Jerry P. ;

Alldredge, Patricia A. ;

Wylie, Todd ;

Walker, Jason ;

Kalicki, Joelle ;

Watson, Mark A. ;

Heath, Sharon ;

Shannon, William D. ;

Varghese, Nobish ;

Nagarajan, Rakesh ;

Westervelt, Peter ;

Tomasson, Michael H. ;

Link, Daniel C. ;

Graubert, Timothy A. ;

DiPersio, John F. ;

Mardis, Elaine R. ;

Wilson, Richard K. .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (25) :2424-2433

[8]

Abnormal platelet count is an independent predictor of mortality in the elderly and is influenced by ethnicity [J].

Msaouel, Pavlos ;

Lam, Anthony P. ;

Gundabolu, Krishna ;

Chrysofakis, Grigorios ;

Yu, Yiting ;

Mantzaris, Ioannis ;

Friedman, Ellen ;

Verma, Amit .

HAEMATOLOGICA, 2014, 99 (05) :930-936

[9]

Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors [J].

Navas, Tony A. ;

Mohindru, Mani ;

Estes, Myka ;

Ma, Jing Ying ;

Sokol, Lubomir ;

Pahanish, Perry ;

Parmar, Simrit ;

Haghnazari, Edwin ;

Zhou, Li ;

Collins, Robert ;

Kerr, Irene ;

Nguyen, Aaron N. ;

Xu, Yin ;

Platanias, Leonidas C. ;

List, Alan A. ;

Higgins, Linda S. ;

Verma, Amit .

BLOOD, 2006, 108 (13) :4170-4177

[10]

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells [J].

Pellagatti, A. ;

Cazzola, M. ;

Giagounidis, A. ;

Perry, J. ;

Malcovati, L. ;

Della Porta, M. G. ;

Jadersten, M. ;

Killick, S. ;

Verma, A. ;

Norbury, C. J. ;

Hellstrom-Lindberg, E. ;

Wainscoat, J. S. ;

Boultwood, J. .

LEUKEMIA, 2010, 24 (04) :756-764

← 1 2 →