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Ref Type

Journal Article

PMID

(27512117)

Authors

Chen LT, Chen CT, Jiaang WT, Chen TY, Butterfield JH, Shih NY, Hsu JT, Lin HY, Lin SF, Tsai HJ

Title

BPR1J373, an Oral Multiple Tyrosine Kinase Inhibitor, Targets c-KIT for the Treatment of c-KIT-Driven Myeloid Leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	10	2016 Oct	2323-2333	Mol Cancer Ther

URL

Abstract Text

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. Mol Cancer Ther; 15(10); 2323-33. ©2016 AACR.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
BPR1J373	BPR1J373	4	0

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BPR1J373			FLT3 Inhibitor 69 KIT Inhibitor 57 PDGFR Inhibitor (Pan) 30 RET Inhibitor 53 SRC Inhibitor 31 VEGFR Inhibitor (Pan) 36	BPR1J373 is a derivative of 5-phenylthiazol-2-ylamine-pyriminide that inhibits multiple tyrosine kinases including KIT, FLT3, VEGFR1, 2, 3, PDGFR-alpha, PDGFR-beta, RET, and SRC, and may result in anti-tumor activity (PMID: 27512117, PMID: 30142229).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT N822K	acute myeloid leukemia	sensitive	BPR1J373	Preclinical - Cell line xenograft	Actionable	In a preclinical study, an acute myeloid leukemia cell line harboring KIT N822K demonstrated sensitivity to treatment with BPR1J373, showing inhibition of Kit phosphorylation and apoptotic induction in culture, and tumor regression in xenograft models (PMID: 27512117).	27512117
KIT D816V	Advanced Solid Tumor	predicted - sensitive	BPR1J373	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT D816V were sensitive to BPR1J373, demonstrating inhibition of Kit phosphorylation (PMID: 27512117).	27512117
KIT V560G KIT D816V	mast-cell leukemia	sensitive	BPR1J373	Preclinical - Cell culture	Actionable	In a preclinical study, a mast-cell leukemia cell line simultaneously harboring KIT D816V and KIT V560G was sensitive to BPR1J373 in culture, demonstrating inhibition of Kit phosphorylation and apoptotic activity (PMID: 27512117).	27512117
KIT wild-type	acute myeloid leukemia	sensitive	BPR1J373	Preclinical - Cell culture	Actionable	In a preclinical study, an acute myeloid leukemia cell line harboring KIT wild-type was sensitive to BPR1J373 in culture, demonstrating apoptotic induction and inhibition of cell proliferation (PMID: 27512117).	27512117

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