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
Pages (from-to)2323-2333
Number of pages11
JournalMolecular Cancer Therapeutics
Volume15
Issue number10
DOIs
Publication statusPublished - 2016 Oct 1

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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

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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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title = "BPR1J373, an oral multiple tyrosine kinase inhibitor, targets c-KIT for the treatment of c-KIT-driven myeloid leukemia",
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.",
author = "Chen, {Li Tzong} and Chen, {Chiung Tong} and Jiaang, {Weir Torn} and Tsai-Yun Chen and Butterfield, {Joseph H.} and Shih, {Neng Yao} and Hsu, {John Tsu An} and Lin, {Hui You} and Lin, {Sheng Fung} and Tsai, {Hui Jen}",
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Chen, LT, Chen, CT, Jiaang, WT, Chen, T-Y, 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

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

TY - JOUR

T1 - BPR1J373, an oral multiple tyrosine kinase inhibitor, targets c-KIT for the treatment of c-KIT-driven myeloid leukemia

AU - Chen, Li Tzong

AU - Chen, Chiung Tong

AU - Jiaang, Weir Torn

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

PY - 2016/10/1

Y1 - 2016/10/1

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.

AB - 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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