AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia

Mirna Golemovic, Srdan Verstovsek, Francis Giles, Jorge Cortes, Taghi Manshouri, Paul W. Manley, Jürgen Mestan, Margaret Dugan, Leila Alland, James D. Griffin, Ralph B. Arlinghaus, Tong Sun, Hagop Kantarjian, Miloslav Beran

Research output: Contribution to journalArticle

Abstract

Resistance to or intolerance of imatinib in patients with Philadelphia chromosome - positive chronic myelogenous leukemia (CML) has encouraged the development of more potent Bcr-Abl inhibitors. AMN107 is a novel, orally bioavailable ATP-competitive inhibitor of Bcr-Abl. The effects of AMN107 were compared with those of imatinib on imatinib-sensitive (KBM5 and KBM7) and imatinib-resistant CML cell lines (KBM5-STI571R1.0 and KBM7-STI571R1.0). Compared with the antiproliferative activity of imatinib, AMN107 was 43 times more potent in KBM5 (IC60 of 11.3 versus 480.5 nmol/L) and 60 times more potent in KBM7 (IC50 of 4.3 versus 259.0 nmol/L) cells. IC50 for AMN107 and imatinib were 2,418.3 and 6,361.4 nmol/L, respectively, in KBM5-STI571R1.0, and 97.2 and 2,497.3 nmol/L, respectively, in KBM7-STI571R1.0 cells. AMN107 inhibited autophosphorylation of Bcr-Abl kinase more effectively than imatinib in all cell lines. They had similar effects on cell cycle progression and apoptotic response in these cell lines. Among severe combined immunodeficient mice bearing KBM5 cells, mean survival times of groups treated with 10, 20, and 30 mg/kg/d of AMN107, starting day 20 after leukemic cell grafting and continuing for 20 days, were 144%, 159%, and 182%, respectively, compared with controls. These results strongly support investigation of the clinical efficacy of AMN107 in patients with CML.

Original languageEnglish (US)
Pages (from-to)4941-4947
Number of pages7
JournalClinical Cancer Research
Volume11
Issue number13
DOIs
StatePublished - Jul 1 2005
Externally publishedYes

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Cell Line
Inhibitory Concentration 50
Philadelphia Chromosome
SCID Mice
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
Imatinib Mesylate
In Vitro Techniques
2-aminopyrimidine
Cell Survival
Cell Cycle
Phosphotransferases
Survival Rate
Adenosine Triphosphate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. / Golemovic, Mirna; Verstovsek, Srdan; Giles, Francis; Cortes, Jorge; Manshouri, Taghi; Manley, Paul W.; Mestan, Jürgen; Dugan, Margaret; Alland, Leila; Griffin, James D.; Arlinghaus, Ralph B.; Sun, Tong; Kantarjian, Hagop; Beran, Miloslav.

In: Clinical Cancer Research, Vol. 11, No. 13, 01.07.2005, p. 4941-4947.

Research output: Contribution to journalArticle

Golemovic, M, Verstovsek, S, Giles, F, Cortes, J, Manshouri, T, Manley, PW, Mestan, J, Dugan, M, Alland, L, Griffin, JD, Arlinghaus, RB, Sun, T, Kantarjian, H & Beran, M 2005, 'AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia', Clinical Cancer Research, vol. 11, no. 13, pp. 4941-4947. https://doi.org/10.1158/1078-0432.CCR-04-2601
Golemovic, Mirna ; Verstovsek, Srdan ; Giles, Francis ; Cortes, Jorge ; Manshouri, Taghi ; Manley, Paul W. ; Mestan, Jürgen ; Dugan, Margaret ; Alland, Leila ; Griffin, James D. ; Arlinghaus, Ralph B. ; Sun, Tong ; Kantarjian, Hagop ; Beran, Miloslav. / AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 13. pp. 4941-4947.
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AU - Golemovic, Mirna

AU - Verstovsek, Srdan

AU - Giles, Francis

AU - Cortes, Jorge

AU - Manshouri, Taghi

AU - Manley, Paul W.

AU - Mestan, Jürgen

AU - Dugan, Margaret

AU - Alland, Leila

AU - Griffin, James D.

AU - Arlinghaus, Ralph B.

AU - Sun, Tong

AU - Kantarjian, Hagop

AU - Beran, Miloslav

PY - 2005/7/1

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N2 - Resistance to or intolerance of imatinib in patients with Philadelphia chromosome - positive chronic myelogenous leukemia (CML) has encouraged the development of more potent Bcr-Abl inhibitors. AMN107 is a novel, orally bioavailable ATP-competitive inhibitor of Bcr-Abl. The effects of AMN107 were compared with those of imatinib on imatinib-sensitive (KBM5 and KBM7) and imatinib-resistant CML cell lines (KBM5-STI571R1.0 and KBM7-STI571R1.0). Compared with the antiproliferative activity of imatinib, AMN107 was 43 times more potent in KBM5 (IC60 of 11.3 versus 480.5 nmol/L) and 60 times more potent in KBM7 (IC50 of 4.3 versus 259.0 nmol/L) cells. IC50 for AMN107 and imatinib were 2,418.3 and 6,361.4 nmol/L, respectively, in KBM5-STI571R1.0, and 97.2 and 2,497.3 nmol/L, respectively, in KBM7-STI571R1.0 cells. AMN107 inhibited autophosphorylation of Bcr-Abl kinase more effectively than imatinib in all cell lines. They had similar effects on cell cycle progression and apoptotic response in these cell lines. Among severe combined immunodeficient mice bearing KBM5 cells, mean survival times of groups treated with 10, 20, and 30 mg/kg/d of AMN107, starting day 20 after leukemic cell grafting and continuing for 20 days, were 144%, 159%, and 182%, respectively, compared with controls. These results strongly support investigation of the clinical efficacy of AMN107 in patients with CML.

AB - Resistance to or intolerance of imatinib in patients with Philadelphia chromosome - positive chronic myelogenous leukemia (CML) has encouraged the development of more potent Bcr-Abl inhibitors. AMN107 is a novel, orally bioavailable ATP-competitive inhibitor of Bcr-Abl. The effects of AMN107 were compared with those of imatinib on imatinib-sensitive (KBM5 and KBM7) and imatinib-resistant CML cell lines (KBM5-STI571R1.0 and KBM7-STI571R1.0). Compared with the antiproliferative activity of imatinib, AMN107 was 43 times more potent in KBM5 (IC60 of 11.3 versus 480.5 nmol/L) and 60 times more potent in KBM7 (IC50 of 4.3 versus 259.0 nmol/L) cells. IC50 for AMN107 and imatinib were 2,418.3 and 6,361.4 nmol/L, respectively, in KBM5-STI571R1.0, and 97.2 and 2,497.3 nmol/L, respectively, in KBM7-STI571R1.0 cells. AMN107 inhibited autophosphorylation of Bcr-Abl kinase more effectively than imatinib in all cell lines. They had similar effects on cell cycle progression and apoptotic response in these cell lines. Among severe combined immunodeficient mice bearing KBM5 cells, mean survival times of groups treated with 10, 20, and 30 mg/kg/d of AMN107, starting day 20 after leukemic cell grafting and continuing for 20 days, were 144%, 159%, and 182%, respectively, compared with controls. These results strongly support investigation of the clinical efficacy of AMN107 in patients with CML.

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