BPR1J373, an oral multiple tyrosine kinase inhibitor, targets c-KIT for the treatment of c-KIT-driven myeloid leukemia

Li Tzong Chen, Chiung Tong Chen, Weir Torn Jiaang, Tsai Yun Chen, Joseph H. Butterfield, Neng Yao Shih, John Tsu An Hsu, Hui You Lin, Sheng Fung Lin, Hui Jen Tsai

Research output: Contribution to journalArticle

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Abstract

Acute myelogenous leukemia (AML) carrying t(8;21)(q22; q22) or inv(16)/t(16;16)(p13;q22) is classified as core binding factor (CBF)-AML and accounts for approximately 15% of AML. c-KIT mutation can be detected in 17%∼46% of CBF-AML and is associated with poor prognosis. c-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22; q22) to cause overt AML. Tyrosine kinase inhibitors (TKI) targeting c-KIT, such as imatinib, has been used successfully to treat c-KIT driven gastrointestinal stromal tumors. However, the effect of TKI on c-KIT-driven leukemia, including CBF-AML and systemic mastocytosis (SM), has not been satisfactory. BPR1J373 is a 5-phenylthiazol-2-ylamine-pyriminide derivative targeting multiple tyrosine kinases. It was shown to inhibit cell proliferation and induce apoptosis in AML cells with constitutively activated c-KIT via inhibiting c-KIT phosphorylation and its downstream signals. The compound induced apoptosis by the mitochondrial intrinsic pathway through upregulation of proapoptotic proteins Bax and Bak and caspase 8 and 9 activation in c-KIT mutant Kasumi-1 cells. Furthermore, it induced cell-cycle arrest via targeting aurora kinase B in c-KIT wild-type KG-1 cells. The antitumor response of BPR1J373 was also shown in subcutaneously grafted SCID mice. BPR1J373 was shown to effectively suppress c-KIT phosphorylation of D816V mutation by treating c-KIT-null COS-1 cells transfected with c-KIT D816V mutant plasmid. In conclusion, BPR1J373 inhibits cell proliferation of c-KIT-driven AML cells via induction of apoptosis and cell-cycle arrest. It is also effective for multiple drug-resistant c-KIT D816V mutation. BPR1J373 deserves further development for clinical use in c-KIT-driven myeloid leukemia.

Original languageEnglish (US)
Pages (from-to)2323-2333
Number of pages11
JournalMolecular Cancer Therapeutics
Volume15
Issue number10
DOIs
StatePublished - Oct 1 2016

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Myeloid Leukemia
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Core Binding Factors
Mutation
Apoptosis
Cell Cycle Checkpoints
bcl-2 Homologous Antagonist-Killer Protein
Aurora Kinase B
Phosphorylation
Cell Proliferation
Systemic Mastocytosis
bcl-2-Associated X Protein
Null Lymphocytes
Gastrointestinal Stromal Tumors
SCID Mice
Caspase 9
Caspase 8
COS Cells
Leukemia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Chen, L. T., Chen, C. T., Jiaang, W. T., Chen, T. Y., Butterfield, J. H., Shih, N. Y., ... Tsai, H. J. (2016). BPR1J373, an oral multiple tyrosine kinase inhibitor, targets c-KIT for the treatment of c-KIT-driven myeloid leukemia. Molecular Cancer Therapeutics, 15(10), 2323-2333. https://doi.org/10.1158/1535-7163.MCT-15-1006

BPR1J373, an oral multiple tyrosine kinase inhibitor, targets c-KIT for the treatment of c-KIT-driven myeloid leukemia. / Chen, Li Tzong; Chen, Chiung Tong; Jiaang, Weir Torn; Chen, Tsai Yun; Butterfield, Joseph H.; Shih, Neng Yao; Hsu, John Tsu An; Lin, Hui You; Lin, Sheng Fung; Tsai, Hui Jen.

In: Molecular Cancer Therapeutics, Vol. 15, No. 10, 01.10.2016, p. 2323-2333.

Research output: Contribution to journalArticle

Chen, LT, Chen, CT, Jiaang, WT, Chen, TY, Butterfield, JH, Shih, NY, Hsu, JTA, Lin, HY, Lin, SF & Tsai, HJ 2016, 'BPR1J373, an oral multiple tyrosine kinase inhibitor, targets c-KIT for the treatment of c-KIT-driven myeloid leukemia', Molecular Cancer Therapeutics, vol. 15, no. 10, pp. 2323-2333. https://doi.org/10.1158/1535-7163.MCT-15-1006
Chen, Li Tzong ; Chen, Chiung Tong ; Jiaang, Weir Torn ; Chen, Tsai Yun ; Butterfield, Joseph H. ; Shih, Neng Yao ; Hsu, John Tsu An ; Lin, Hui You ; Lin, Sheng Fung ; Tsai, Hui Jen. / BPR1J373, an oral multiple tyrosine kinase inhibitor, targets c-KIT for the treatment of c-KIT-driven myeloid leukemia. In: Molecular Cancer Therapeutics. 2016 ; Vol. 15, No. 10. pp. 2323-2333.
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abstract = "Acute myelogenous leukemia (AML) carrying t(8;21)(q22; q22) or inv(16)/t(16;16)(p13;q22) is classified as core binding factor (CBF)-AML and accounts for approximately 15{\%} of AML. c-KIT mutation can be detected in 17{\%}∼46{\%} of CBF-AML and is associated with poor prognosis. c-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22; q22) to cause overt AML. Tyrosine kinase inhibitors (TKI) targeting c-KIT, such as imatinib, has been used successfully to treat c-KIT driven gastrointestinal stromal tumors. However, the effect of TKI on c-KIT-driven leukemia, including CBF-AML and systemic mastocytosis (SM), has not been satisfactory. BPR1J373 is a 5-phenylthiazol-2-ylamine-pyriminide derivative targeting multiple tyrosine kinases. It was shown to inhibit cell proliferation and induce apoptosis in AML cells with constitutively activated c-KIT via inhibiting c-KIT phosphorylation and its downstream signals. The compound induced apoptosis by the mitochondrial intrinsic pathway through upregulation of proapoptotic proteins Bax and Bak and caspase 8 and 9 activation in c-KIT mutant Kasumi-1 cells. Furthermore, it induced cell-cycle arrest via targeting aurora kinase B in c-KIT wild-type KG-1 cells. The antitumor response of BPR1J373 was also shown in subcutaneously grafted SCID mice. BPR1J373 was shown to effectively suppress c-KIT phosphorylation of D816V mutation by treating c-KIT-null COS-1 cells transfected with c-KIT D816V mutant plasmid. In conclusion, BPR1J373 inhibits cell proliferation of c-KIT-driven AML cells via induction of apoptosis and cell-cycle arrest. It is also effective for multiple drug-resistant c-KIT D816V mutation. BPR1J373 deserves further development for clinical use in c-KIT-driven myeloid leukemia.",
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AU - Chen, Chiung Tong

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AU - Chen, Tsai Yun

AU - Butterfield, Joseph H.

AU - Shih, Neng Yao

AU - Hsu, John Tsu An

AU - Lin, Hui You

AU - Lin, Sheng Fung

AU - Tsai, Hui Jen

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N2 - Acute myelogenous leukemia (AML) carrying t(8;21)(q22; q22) or inv(16)/t(16;16)(p13;q22) is classified as core binding factor (CBF)-AML and accounts for approximately 15% of AML. c-KIT mutation can be detected in 17%∼46% of CBF-AML and is associated with poor prognosis. c-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22; q22) to cause overt AML. Tyrosine kinase inhibitors (TKI) targeting c-KIT, such as imatinib, has been used successfully to treat c-KIT driven gastrointestinal stromal tumors. However, the effect of TKI on c-KIT-driven leukemia, including CBF-AML and systemic mastocytosis (SM), has not been satisfactory. BPR1J373 is a 5-phenylthiazol-2-ylamine-pyriminide derivative targeting multiple tyrosine kinases. It was shown to inhibit cell proliferation and induce apoptosis in AML cells with constitutively activated c-KIT via inhibiting c-KIT phosphorylation and its downstream signals. The compound induced apoptosis by the mitochondrial intrinsic pathway through upregulation of proapoptotic proteins Bax and Bak and caspase 8 and 9 activation in c-KIT mutant Kasumi-1 cells. Furthermore, it induced cell-cycle arrest via targeting aurora kinase B in c-KIT wild-type KG-1 cells. The antitumor response of BPR1J373 was also shown in subcutaneously grafted SCID mice. BPR1J373 was shown to effectively suppress c-KIT phosphorylation of D816V mutation by treating c-KIT-null COS-1 cells transfected with c-KIT D816V mutant plasmid. In conclusion, BPR1J373 inhibits cell proliferation of c-KIT-driven AML cells via induction of apoptosis and cell-cycle arrest. It is also effective for multiple drug-resistant c-KIT D816V mutation. BPR1J373 deserves further development for clinical use in c-KIT-driven myeloid leukemia.

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