BMS-777607 - CAS 1025720-94-8
Catalog number: 1025720-94-8
Category: Inhibitor
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Molecular Formula:
C25H19ClF2N4O4
Molecular Weight:
512.893
COA:
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Targets:
c-Met/HGFR
Description:
BMS-777607 is a novel prodrug of the dual Met/VEGFR-2 inhibitor.
Appearance:
white solid powder
Synonyms:
BMS817378; BMS 817378; BMS-817378; BMS 777607; BMS-777607; BMS777607; ASLAN 002; ASLAN-002; ASLAN002.
MSDS:
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Current Developer:
Simcere and Bristol-Myers Squibb
1.Synergistic activities of MET/RON inhibitor BMS-777607 and mTOR inhibitor AZD8055 to polyploid cells derived from pancreatic cancer and cancer stem cells.
Zeng JY1, Sharma S, Zhou YQ, Yao HP, Hu X, Zhang R, Wang MH. Mol Cancer Ther. 2014 Jan;13(1):37-48. doi: 10.1158/1535-7163.MCT-13-0242. Epub 2013 Nov 14.
Tyrosine kinase inhibitor BMS-777067 is an inhibitor of RON/MET receptor tyrosine kinases currently under clinical trials. Here, we report the synergistic activity of BMS-777607 in combination with mTOR inhibitor AZD8055 in killing chemoresistant pancreatic cancer and cancer stem cells. Treatment of pancreatic cancer L3.6pl cells with BMS-777607 alone inhibited clonogenic growth and moderately induced apoptotic death. However, BMS-777607 caused extensive polyploidy in L3.6pl cells through inhibition of aurora kinase B activity, independent of RON expression. In contrast, L3.6pl-derived cancer stem cells were highly resistant to BMS-777607-induced growth inhibition and apoptosis. The effect of BMS-777607 on induction of cancer stem cell polyploidy was also weak. BMS-777607-induced polyploidy features a predominant cell population with 8N chromosome content in both L3.6pl and cancer stem cells. These cells also showed decreased sensitivity toward chemotherapeutics by increased survival of IC(50) values in response to doxorubicin, cisplatin, methotrexate, 5-fluorouracial, and gemcitabine.
2.Prevention of BMS-777607-induced polyploidy/senescence by mTOR inhibitor AZD8055 sensitizes breast cancer cells to cytotoxic chemotherapeutics.
Sharma S1, Yao HP2, Zhou YQ3, Zhou J4, Zhang R5, Wang MH6. Mol Oncol. 2014 May;8(3):469-82. doi: 10.1016/j.molonc.2013.12.014. Epub 2014 Jan 2.
Targeted inhibition of MET/RON signaling by tyrosine kinase inhibitor BMS-777607 for cancer treatment is currently under clinical trials. We have previously shown that BMS-777607 induces chemoresistance in vitro by causing polyploidy, which hampers therapeutic efficacy. Here, we studied polyploidy-associated senescence induced by BMS-777607 in breast cancer cells and its prevention by mTOR inhibitor AZD8055, leading to increased chemosensitivity. In breast cancer T-47D and ZR-75-1 cells, BMS-777607 induced phenotypic changes including enlarged cellular size, flattened morphology, increased DNA content, and activity of senescence-associated β-galactosidase. These changes were accompanied by increased p21/WAF1 expression and decreased Retinoblastoma Ser(780) phosphorylation, indicating that BMS-777607 induces not only polyploidy but also senescence. The appearance of senescence was associated with polyploidy in which β-galactosidase is exclusively expressed in polyploid cells.
3.Discovery of novel type II c-Met inhibitors based on BMS-777607.
Zhang W1, Ai J2, Shi D3, Peng X2, Ji Y2, Liu J1, Geng M4, Li Y5. Eur J Med Chem. 2014 Jun 10;80:254-66. doi: 10.1016/j.ejmech.2014.04.056. Epub 2014 Apr 21.
Twenty-two new analogs based on the structure of BMS-777607 were designed, synthesized, and evaluated to determine their biological activities. Compounds bearing a cyclic sulfonamide or α-chloropiperidone scaffold exhibited good activity, which may provide a new basis for further structural optimization. Quinoline-containing analogs exhibited better results than did their counterparts with an aminopyrimidine, aminopyridine, or pyrrolopyridine unit. Two analogs, 22d and 22e, stood out as the most potent c-Met inhibitors with IC50s of 0.9 and 1.7 nM, respectively. These two compounds were more potent than BMS-777607 in enzymatic inhibition and cell proliferation studies.
4.BMS-777607 promotes megakaryocytic differentiation and induces polyploidization in the CHRF-288-11 cells.
Nurhayati RW1, Ojima Y, Taya M. Hum Cell. 2015 Apr;28(2):65-72. doi: 10.1007/s13577-014-0102-2. Epub 2014 Oct 11.
Introduction of a polyploidy inducer is a promising strategy to achieve a high level of polyploidization during megakaryocytic (MK) differentiation. Here, we report that a multi-kinase inhibitor, BMS-777607, is a potent polyploidy inducer for elevating high ploidy cell formation in the MK-differentiated CHRF-288-11 (CHRF) cells. Our result showed that BMS-777607 strongly inhibited cell division without affecting cell viability when detected at day 1 after treatment. As a consequence, the high ploidy (≥8N) cells were accumulated in culture for 8 days, with an increase from 16.2 to 75.2 % of the total cell population. The elevated polyploidization was accompanied by the increased expression level of MK marker, CD41 (platelet glycoprotein IIb/IIIa, GPIIb/IIIa), suggesting that BMS-777607 promoted both polyploidization and commitment of MK-differentiated CHRF cells. Platelet-like fragments (PFs) were released by mature CHRF cells. Based on a flow cytometry assay, it was found that the PFs produced from BMS-777607-treated cells tended to have larger size and higher expression of GPIIb/IIIa, a receptor for platelet adhesion.
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