LY2801653 - CAS 1206799-15-6
Catalog number:
1206799-15-6
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
COA:
Inquire
Targets:
c-Met/HGFR
Description:
LY2801653 is an orally available, small molecule inhibitor of the proto-oncogene c-Met with potential antineoplastic activity.
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Purity:
>98%
Appearance:
Solid powder
Synonyms:
LY-2801653; LY 2801653
MSDS:
Inquire
Current Developer:
Eli Lilly.
1.Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non-small cell lung cancer.
Kawada I1, Hasina R, Arif Q, Mueller J, Smithberger E, Husain AN, Vokes EE, Salgia R. Cancer Res. 2014 Feb 1;74(3):884-95. doi: 10.1158/0008-5472.CAN-12-3583. Epub 2013 Dec 4.
Lung cancer is a heterogeneous disease encompassing a wide array of genetic abnormalities. The MET receptor tyrosine kinase is altered in many lung cancers, especially non-small cell lung cancer (NSCLC), and clinical trials of MET inhibitors that are under way are documenting cases of acquired resistance. On the basis of the evidence that the RON tyrosine kinase receptor can also be overexpressed in NSCLC, we evaluated the potent MET/RON dual kinase inhibitor LY2801653 in this setting. LY2801653 was more efficacious than the MET/ALK/RON/ROS inhibitor crizotinib with a distinct pattern of downstream signaling effects. Using the PamGene platform, we found that inhibition of MET and RON was associated with decreased phosphorylation of CBL, PI3K, and STAT3. In classic and orthotopic mouse xenograft models of lung cancer, LY2801653 decreased tumor growth, dramatically inhibiting mitotic events and angiogenesis. Taken together, our results argued that specific targeting of the MET/RON kinases could provide robust inhibition of cell proliferation and tumor outgrowth in multiple in vitro and in vivo models of NSCLC.
2.Inhibition of tumor growth and metastasis in non-small cell lung cancer by LY2801653, an inhibitor of several oncokinases, including MET.
Wu W1, Bi C, Credille KM, Manro JR, Peek VL, Donoho GP, Yan L, Wijsman JA, Yan SB, Walgren RA. Clin Cancer Res. 2013 Oct 15;19(20):5699-710. doi: 10.1158/1078-0432.CCR-13-1758. Epub 2013 Aug 29.
PURPOSE: Lung cancer is the leading cause of cancer-related death worldwide. Sustained activation, overexpression, or mutation of the MET pathway is associated with a poor prognosis in a variety of tumors, including non-small cell lung cancer (NSCLC), implicating the MET pathway as a potential therapeutic target for lung cancer. Previously, we reported on the development of LY2801653: a novel, orally bioavailable oncokinase inhibitor with MET as one of its targets. Here, we discuss the evaluation of LY2801653 in both preclinical in vitro and in vivo NSCLC models. Experimental Design/
3.LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models.
Yan SB1, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui YH, Huss KL, Konicek BW, Manro JR, Shih C, Stewart JA, Stewart TR, Stout SL, Uhlik MT, Um SL, Wang Y, Wu W, Yan L, Yang WJ, Zhong B, Walgren RA. Invest New Drugs. 2013 Aug;31(4):833-44. doi: 10.1007/s10637-012-9912-9. Epub 2012 Dec 29.
The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia, including cell proliferation, survival, apoptosis, scattering and motility, invasion, and angiogenesis. MET over-expression (with or without gene amplification), aberrant autocrine or paracrine ligand production, and missense MET mutations are mechanisms that lead to activation of the MET pathway in tumors and are associated with poor prognostic outcome. We report here preclinical development of a potent, orally bioavailable, small-molecule inhibitor LY2801653 targeting MET kinase. LY2801653 is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a dissociation constant (Ki) of 2 nM, a pharmacodynamic residence time (Koff) of 0.00132 min(-1) and t1/2 of 525 min. LY2801653 demonstrated in vitro effects on MET pathway-dependent cell scattering and cell proliferation; in vivo anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects.
4.Targeting c-MET by LY2801653 for treatment of cholangiocarcinoma.
Barat S1, Bozko P1, Chen X1, Scholta T1, Hanert F1, Götze J1, Malek NP1, Wilkens L2, Plentz RR1. Mol Carcinog. 2016 Jan 12. doi: 10.1002/mc.22449. [Epub ahead of print]
Palliative treatment options for human cholangiocarcinoma (CCC) are quite limited and new therapeutic strategies are of utmost need. c-MET has been shown to be deregulated in many cancers, but the role of c-MET in the carcinogenesis of CCC remains unclear. The main purpose of this study is to evaluate the expression and also to investigate the role of c-MET and its effective inhibition for the treatment of CCC. In this study we investigated the effects of LY2801653, a small-molecule inhibitor with potent activity against MET kinase, in human CCC cell lines and in vivo using a xenograft mouse model. We have investigated the role of c-MET and its inhibitory effects on migration, invasion, colony formation, MET downstream targets, and CCC tumor growth. We also analyzed the role of apoptosis and senescence as well as the influence of hypoxia in this context. c-MET and p-MET were expressed in 72% and 12.5% of human CCC tissues and in TFK-1, SZ-1 cell lines.
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CAS 1206799-15-6 LY2801653

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