Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma

Xiaojing Wang, Anthony L. Sinn, Karen Pollok, George Sandusky, Shuhong Zhang, Li Chen, Jing Liang, Colin D. Crean, Attaya Suvannasankha, Rafat Abonour, Carolyn Sidor, Mark R. Bray, Sherif Farag

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Summary ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against aurora and multiple receptor tyrosine kinases. We investigated the activity of ENMD-2076 against multiple myeloma (MM) cells in vitro and in vivo. ENMD-2076 showed significant cytotoxicity against MM cell lines and primary cells, with minimal cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibited the phosphoinositide 3-kinase/AKT pathway and downregulated survivin and X-linked inhibitor of apoptosis as early as 6 h after treatment. With longer treatment (24-48 h), ENMD-2076 also inhibited aurora A and B kinases, and induced G2/M cell cycle arrest. In non-obese diabetic/severe combined immunodeficient mice implanted with H929 human plasmacytoma xenografts, oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) resulted in a dose-dependent inhibition of tumour growth. Immunohistochemical staining of excised tumours showed significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3 at all dose levels compared to tumours from vehicle-treated mice. In addition, a significant reduction in p-FGFR3 was observed on Western blot. ENMD-2076 shows significant activity against MM cells in vitro and in vivo, and acts on several pathways important for myeloma cell growth and survival. These results provide preclinical rationale for clinical investigation of ENMD-2076 in MM.

Original languageEnglish
Pages (from-to)313-325
Number of pages13
JournalBritish Journal of Haematology
Volume150
Issue number3
DOIs
StatePublished - Aug 2010

Fingerprint

Aurora Kinases
Multiple Myeloma
Protein-Tyrosine Kinases
Aurora Kinase B
Aurora Kinase A
G2 Phase Cell Cycle Checkpoints
Neoplasms
Plasmacytoma
1-Phosphatidylinositol 4-Kinase
SCID Mice
ENMD 2076
Receptor Protein-Tyrosine Kinases
Growth
Heterografts
Caspase 3
Histones
Cell Survival
Down-Regulation
Western Blotting
Apoptosis

Keywords

  • apoptosis
  • multiple myeloma
  • tyrosine kinase

ASJC Scopus subject areas

  • Hematology

Cite this

Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma. / Wang, Xiaojing; Sinn, Anthony L.; Pollok, Karen; Sandusky, George; Zhang, Shuhong; Chen, Li; Liang, Jing; Crean, Colin D.; Suvannasankha, Attaya; Abonour, Rafat; Sidor, Carolyn; Bray, Mark R.; Farag, Sherif.

In: British Journal of Haematology, Vol. 150, No. 3, 08.2010, p. 313-325.

Research output: Contribution to journalArticle

Wang, Xiaojing ; Sinn, Anthony L. ; Pollok, Karen ; Sandusky, George ; Zhang, Shuhong ; Chen, Li ; Liang, Jing ; Crean, Colin D. ; Suvannasankha, Attaya ; Abonour, Rafat ; Sidor, Carolyn ; Bray, Mark R. ; Farag, Sherif. / Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma. In: British Journal of Haematology. 2010 ; Vol. 150, No. 3. pp. 313-325.
@article{052a537f96f540468da0f730f97da4ed,
title = "Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma",
abstract = "Summary ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against aurora and multiple receptor tyrosine kinases. We investigated the activity of ENMD-2076 against multiple myeloma (MM) cells in vitro and in vivo. ENMD-2076 showed significant cytotoxicity against MM cell lines and primary cells, with minimal cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibited the phosphoinositide 3-kinase/AKT pathway and downregulated survivin and X-linked inhibitor of apoptosis as early as 6 h after treatment. With longer treatment (24-48 h), ENMD-2076 also inhibited aurora A and B kinases, and induced G2/M cell cycle arrest. In non-obese diabetic/severe combined immunodeficient mice implanted with H929 human plasmacytoma xenografts, oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) resulted in a dose-dependent inhibition of tumour growth. Immunohistochemical staining of excised tumours showed significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3 at all dose levels compared to tumours from vehicle-treated mice. In addition, a significant reduction in p-FGFR3 was observed on Western blot. ENMD-2076 shows significant activity against MM cells in vitro and in vivo, and acts on several pathways important for myeloma cell growth and survival. These results provide preclinical rationale for clinical investigation of ENMD-2076 in MM.",
keywords = "apoptosis, multiple myeloma, tyrosine kinase",
author = "Xiaojing Wang and Sinn, {Anthony L.} and Karen Pollok and George Sandusky and Shuhong Zhang and Li Chen and Jing Liang and Crean, {Colin D.} and Attaya Suvannasankha and Rafat Abonour and Carolyn Sidor and Bray, {Mark R.} and Sherif Farag",
year = "2010",
month = "8",
doi = "10.1111/j.1365-2141.2010.08248.x",
language = "English",
volume = "150",
pages = "313--325",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma

AU - Wang, Xiaojing

AU - Sinn, Anthony L.

AU - Pollok, Karen

AU - Sandusky, George

AU - Zhang, Shuhong

AU - Chen, Li

AU - Liang, Jing

AU - Crean, Colin D.

AU - Suvannasankha, Attaya

AU - Abonour, Rafat

AU - Sidor, Carolyn

AU - Bray, Mark R.

AU - Farag, Sherif

PY - 2010/8

Y1 - 2010/8

N2 - Summary ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against aurora and multiple receptor tyrosine kinases. We investigated the activity of ENMD-2076 against multiple myeloma (MM) cells in vitro and in vivo. ENMD-2076 showed significant cytotoxicity against MM cell lines and primary cells, with minimal cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibited the phosphoinositide 3-kinase/AKT pathway and downregulated survivin and X-linked inhibitor of apoptosis as early as 6 h after treatment. With longer treatment (24-48 h), ENMD-2076 also inhibited aurora A and B kinases, and induced G2/M cell cycle arrest. In non-obese diabetic/severe combined immunodeficient mice implanted with H929 human plasmacytoma xenografts, oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) resulted in a dose-dependent inhibition of tumour growth. Immunohistochemical staining of excised tumours showed significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3 at all dose levels compared to tumours from vehicle-treated mice. In addition, a significant reduction in p-FGFR3 was observed on Western blot. ENMD-2076 shows significant activity against MM cells in vitro and in vivo, and acts on several pathways important for myeloma cell growth and survival. These results provide preclinical rationale for clinical investigation of ENMD-2076 in MM.

AB - Summary ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against aurora and multiple receptor tyrosine kinases. We investigated the activity of ENMD-2076 against multiple myeloma (MM) cells in vitro and in vivo. ENMD-2076 showed significant cytotoxicity against MM cell lines and primary cells, with minimal cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibited the phosphoinositide 3-kinase/AKT pathway and downregulated survivin and X-linked inhibitor of apoptosis as early as 6 h after treatment. With longer treatment (24-48 h), ENMD-2076 also inhibited aurora A and B kinases, and induced G2/M cell cycle arrest. In non-obese diabetic/severe combined immunodeficient mice implanted with H929 human plasmacytoma xenografts, oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) resulted in a dose-dependent inhibition of tumour growth. Immunohistochemical staining of excised tumours showed significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3 at all dose levels compared to tumours from vehicle-treated mice. In addition, a significant reduction in p-FGFR3 was observed on Western blot. ENMD-2076 shows significant activity against MM cells in vitro and in vivo, and acts on several pathways important for myeloma cell growth and survival. These results provide preclinical rationale for clinical investigation of ENMD-2076 in MM.

KW - apoptosis

KW - multiple myeloma

KW - tyrosine kinase

UR - http://www.scopus.com/inward/record.url?scp=77954599491&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954599491&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2141.2010.08248.x

DO - 10.1111/j.1365-2141.2010.08248.x

M3 - Article

VL - 150

SP - 313

EP - 325

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 3

ER -