BPR1J373, an Oral Multiple Tyrosine Kinase Inhibitor, Targets c-KIT for the Treatment of <i>c-KIT</i>–Driven Myeloid Leukemia

Chen, Li Tzong; Chen, Chiung Tong; Jiaang, Weir Torn; Chen, Tsai Yun; Butterfield, Joseph H.; Shih, Neng Yao; Hsu, John; Lin, Hui You; Lin, Shiu-Shiung; Tsai, Hung-Pei

doi:10.1158/1535-7163.mct-15-1006

Cited by 10 publications

(17 citation statements)

References 48 publications

(55 reference statements)

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“…Furthermore, BPR1J373 also showed a remarkable potency in the suppression of KIT activation in COS‐1 transfectants with all 4 double mutations, whereas imatinib, sunitinib, nilotinib, and regorafenib showed variable effects on suppression of KIT phosphorylation (Figure B). For D816V in exon 17, which is resistant to imatinib, sunitinib, and nilotinib, BPR1J373 still suppressed KIT phosphorylation in a time‐dependent manner, whereas the other 3 tyrosine kinase inhibitors did not, as shown previously …”

Section: Resultssupporting

confidence: 78%

“…BPR1J373 also exerted an inhibitory effect on Aurora kinase A and B in GIST882 cells, as shown in , which suggests that the induction of apoptosis in GIST882 might occur through targeting of KIT and possibly Aurora kinase A and B. We have previously shown that BPR1J373 was effective in suppressing phosphorylation of Aurora kinase B and inducing polyploidy of the acute myeloid leukemia cell line KG‐1 . Although BPR1J373 has both anti‐Aurora kinase A and B activity, its inhibition on Aurora kinase A or B might depend on the cellular contents of different cancer cell types.…”

Section: Discussionmentioning

confidence: 73%

“…For D816V in exon 17, which is resistant to imatinib, sunitinib, and nilotinib, BPR1J373 still suppressed KIT phosphorylation in a time-dependent manner, whereas the other 3 tyrosine kinase inhibitors did not, as shown previously. 26…”

Section: Bpr1j373 Suppressed Kit Activation Of Cos-1 Cells With Kitmentioning

confidence: 99%

“…BPR1J373, a 5‐phenylthiazol‐2‐ylamine‐pyriminide derivative, is a multitargeted kinase inhibitor with potent inhibitory activity against fms like tyrosine kinase 3, KIT, vascular endothelial growth factor receptor (VEGFR), Aurora A, Aurora B, PDGFRα, PDGFRβ, reannanged during transfection, and sarcoma in preliminary kinase profiling. The structure of BPR1J373 was shown previously . The antikinase profile of BPR1J373 is presented in .…”

Section: Introductionmentioning

confidence: 97%

“…The structure of BPR1J373 was shown previously. 26 The antikinase profile of BPR1J373 is presented in Figure S1. BPR1J373 has been shown to inhibit proliferation of KIT-driven acute myeloid leukemia cells in vitro and in vivo.…”

mentioning

confidence: 99%

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BPR1J373, a novel multitargeted kinase inhibitor, effectively suppresses the growth of gastrointestinal stromal tumor

et al. 2018

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Gastrointestinal stromal tumor (GIST) is a type of KIT‐driven cancer. KIT gene mutations are found in approximately 80% of GISTs, and most of these mutations occur in exon 9 and exon 11. Imatinib has been successfully used as a first‐line treatment for advanced GIST, with a significant improvement in progression‐free survival (PFS) and overall survival. However, disease progression might develop due to primary or secondary resistance to imatinib. Sunitinib and regorafenib have been approved as second‐ and third‐line treatments for advanced GIST patients, with median PFS values of 6.8 and 4.8 months, respectively. However, these relatively modest improvements in PFS underscore the need for more effective KIT inhibitors. BPR1J373 is a multitargeted kinase inhibitor that has been shown to inhibit the proliferation of KIT‐driven acute myeloid leukemia cells in vitro and in vivo. In this study, we found that BPR1J373 inhibited proliferation and induced apoptosis by targeting KIT in GIST cells with KIT gene mutations. BPR1J373 also induced cell cycle arrest and senescent change in KIT‐mutant GIST48 cells, probably by targeting aurora kinase A. In the KIT‐null COS‐1 cell‐based system, BPR1J373 effectively inhibited KIT with single or double mutations of KIT developed in GIST. The antiproliferative effect was also consistently evident in GIST430 tumor‐grafted mice. The results suggest that BPR1J373 could be a potential anticancer drug for GIST and deserves further investigation for clinical applications.

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Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 73%

Section: Bpr1j373 Suppressed Kit Activation Of Cos-1 Cells With Kitmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

mentioning

confidence: 99%

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BPR1J373, a novel multitargeted kinase inhibitor, effectively suppresses the growth of gastrointestinal stromal tumor

et al. 2018

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Polyphyllin I Inhibits Proliferation and Induces Apoptosis by Downregulating AML1‐ETO and Suppressing C‐KIT/Akt Signaling in t(8;21) Acute Myeloid Leukemia

Chai

et al. 2018

Chemistry & Biodiversity

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Polyphyllin I (PPI), a bioactive constituent extracted from traditional medicinal herbs, is cytotoxic to several cancer types. However, whether PPI can be used to treat t(8;21) acute myeloid leukemia (AML) cells requires further investigation. Here, we determined the inhibitory effects of PPI on t(8;21) AML cells by Cell Counting Kit-8 (CCK-8) and the trypan blue dye exclusion assay. DAPI staining and Wright-Giemsa staining were performed to check for apoptosis. Detection of apoptotic protein and AML1-ETO signaling protein expression were conducted by Western blot analysis. Our results suggested that PPI decreased growth and induced apoptosis in a dosage-dependent manner in the t(8;21) AML cell line Kasumi-1. PPI significantly downregulated AML1-ETO expression in a dosage- and time-dependent manner. PPI also upregulated P21 and downregulated survivin expression by reducing AML1-ETO. Mechanistically, PPI significantly reduced the expression of C-KIT, another therapeutic target for AML with t(8;21), followed by inhibition of Akt signaling. These results suggest that PPI can suppress growth and induce apoptosis of t(8;21) AML by suppressing the AML1-ETO and C-KIT/Akt signaling pathways. Therefore, PPI may be an anticancer therapeutic to treat t(8;21) AML.

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Efficacy of a combination therapy targeting CDK4/6 and autophagy in a mouse xenograft model of t(8;21) acute myeloid leukemia

Matsuo¹,

Nakatani²,

Harata³

et al. 2021

Biochemistry and Biophysics Reports

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One of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML) is t(8;21). Although patients with t(8;21) AML have a more favorable prognosis than other cytogenetic subgroups, relapse is still common and novel therapeutic approaches are needed. A recent study showed that t(8;21) AML is characterized by CCND2 deregulation and that co-inhibition of CDK4/6 and autophagy induces apoptosis in t(8;21) AML cells. In this study, we examined the in vivo effects of co-inhibiting CDK4/6 and autophagy. We used a mouse model in which t(8;21)-positive Kasumi-1 cells were subcutaneously inoculated into NOD/Shi-scid IL2Rg null mice. The mice were treated with the autophagy inhibitor chloroquine (CQ), a CDK4/6 inhibitor (either abemaciclib or palbociclib), or a CDK4/6 inhibitor plus CQ. After 20 days of treatment, tumor volume was measured, and immunostaining and transmission electron microscopy observations were performed. There was no change in tumor growth in CQ-treated mice. However, mice treated with a CDK4/6 inhibitor plus CQ had significantly less tumor growth than mice treated with a CDK4/6 inhibitor alone. CDK4/6 inhibitor treatment increased the formation of autophagosomes. The number of single-strand DNA-positive (apoptotic) cells was significantly higher in the tumors of mice treated with a CDK4/6 inhibitor plus CQ than in mice treated with either CQ or a CDK4/6 inhibitor. These results show that CDK4/6 inhibition induces autophagy, and that co-inhibition of CDK4/6 and autophagy induces apoptosis in t(8;21) AML cells in vivo . The results suggest that inhibiting CDK4/6 and autophagy could be a novel and promising therapeutic strategy in t(8;21) AML.

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

Cited by 10 publications

References 48 publications

BPR1J373, a novel multitargeted kinase inhibitor, effectively suppresses the growth of gastrointestinal stromal tumor

BPR1J373, a novel multitargeted kinase inhibitor, effectively suppresses the growth of gastrointestinal stromal tumor

Polyphyllin I Inhibits Proliferation and Induces Apoptosis by Downregulating AML1‐ETO and Suppressing C‐KIT/Akt Signaling in t(8;21) Acute Myeloid Leukemia

Efficacy of a combination therapy targeting CDK4/6 and autophagy in a mouse xenograft model of t(8;21) acute myeloid leukemia

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