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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 Molecular cancer therapeutics
Vol 15
Issue 10
Date 2016 Oct
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
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
BPR1J373 BPR1J373 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
BPR1J373 FLT3 Inhibitor 55 KIT Inhibitor 51 PDGFR Inhibitor (Pan) 27 RET Inhibitor 39 SRC Inhibitor 29 VEGFR Inhibitor (Pan) 32 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).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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
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