| Title |
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
|
|---|---|
| Published in |
Investigational New Drugs, December 2012
|
| DOI | 10.1007/s10637-012-9912-9 |
| Pubmed ID | |
| Authors |
S. Betty Yan, Victoria L. Peek, Rose Ajamie, Sean G. Buchanan, Jeremy R. Graff, Steven A. Heidler, Yu-Hua Hui, Karen L. Huss, Bruce W. Konicek, Jason R. Manro, Chuan Shih, Julie A. Stewart, Trent R. Stewart, Stephanie L. Stout, Mark T. Uhlik, Suzane L. Um, Yong Wang, Wenjuan Wu, Lei Yan, Wei J. Yang, Boyu Zhong, Richard A. Walgren |
| Abstract |
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. LY2801653 also maintained potency against 13 MET variants, each bearing a single-point mutation. In subsequent nonclinical characterization, LY2801653 was found to have potent activity against several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2 and against the serine/threonine kinases MKNK1/2. The potential value of MET and other inhibited targets within a number of malignancies (such as colon, bile ducts, and lung) is discussed. LY2801653 is currently in phase 1 clinical testing in patients with advanced cancer (trial I3O-MC-JSBA, NCT01285037). |
Mendeley readers
The data shown below were compiled from readership statistics for 101 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 3 | 3% |
| Hungary | 1 | <1% |
| Netherlands | 1 | <1% |
| Austria | 1 | <1% |
| Unknown | 95 | 94% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 27 | 27% |
| Student > Ph. D. Student | 19 | 19% |
| Other | 8 | 8% |
| Student > Master | 8 | 8% |
| Student > Bachelor | 7 | 7% |
| Other | 16 | 16% |
| Unknown | 16 | 16% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 20 | 20% |
| Medicine and Dentistry | 17 | 17% |
| Agricultural and Biological Sciences | 17 | 17% |
| Chemistry | 12 | 12% |
| Pharmacology, Toxicology and Pharmaceutical Science | 7 | 7% |
| Other | 8 | 8% |
| Unknown | 20 | 20% |
Attention Score in Context
This research output has an Altmetric Attention Score of 13. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 15 April 2015.
All research outputs
#2,273,056
of 22,729,647 outputs
Outputs from Investigational New Drugs
#48
of 1,167 outputs
Outputs of similar age
#23,763
of 280,355 outputs
Outputs of similar age from Investigational New Drugs
#1
of 9 outputs
Altmetric has tracked 22,729,647 research outputs across all sources so far. Compared to these this one has done well and is in the 89th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,167 research outputs from this source. They receive a mean Attention Score of 4.7. This one has done particularly well, scoring higher than 95% of its peers.
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We're also able to compare this research output to 9 others from the same source and published within six weeks on either side of this one. This one has scored higher than all of them