Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Inhibitors of receptor tyrosine kinases (rtk) and methods of use thereof

A technology of tyrosine kinase and amino acid, which is applied to the inhibitor of receptor tyrosine kinase (RTK) and its application field, can solve the problem of not knowing what the structural basis of receptor tyrosine kinase is.

Inactive Publication Date: 2012-10-31
YALE UNIV
View PDF274 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although tyrosine phosphorylation plays an important role in cell signaling, it is unclear what is the structural basis for trans autophosphorylation of receptor tyrosine kinases

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Inhibitors of receptor tyrosine kinases (rtk) and methods of use thereof
  • Inhibitors of receptor tyrosine kinases (rtk) and methods of use thereof
  • Inhibitors of receptor tyrosine kinases (rtk) and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0244] Preparation of polyclonal antibody of the present invention

[0245] Polyclonal antibodies of the invention can be produced by a variety of techniques well known in the art. Polyclonal antibodies are derived from different B cell lines and therefore recognize multiple epitopes on the same antigen. Polyclonal antibodies are typically produced by immunizing a suitable mammal with an antigen of interest (eg, the asymmetric contact interface of an RTK). Animals frequently used to generate polyclonal antibodies are chickens, goats, guinea pigs, hamsters, horses, mice, rats, sheep and most commonly rabbits. Standard methods for producing polyclonal antibodies are widely known in the art and can be combined with methods of the present invention (e.g. research.cm.utexas.edu / bkitto / Kittolabpage / Protocols / Immunology / PAb.html; U.S. Patents 4,719,290, 6,335,163, 5,789,208, 2,520,076, 2,543,215, and 3,597,409, the entire contents of which are incorporated herein by reference). ...

Embodiment 1

[0343] Example 1: Asymmetric dimerization interface during autophosphorylation of FGFR1.

[0344] Structure of activated FGFR1 kinase in complex with a phospholipase Cγ (PLCγ) fragment (Bae et al. (2009) Cell, 138(3):512-524) shows two symmetrically related activated kinase domains forming an asymmetric dimerization body showing in vivo trans-autophosphorylation of Y583 in the kinase insert region ( Figure 1A and Figure 1B ). The asymmetric arrangement of the two kinase molecules is formed between the activation fragment, the tip of the nucleotide-binding loop, the β3-αC loop, the β4-β5 loop, and the N-terminal region of the αC helix in the kinase molecule used as enzyme (E). The interface formed between the kinase insertion and the residues between the C-lobe helix αF-αG of the second kinase molecule used as the substrate (S) is mediated by ( Figure 1C and Figure 1D ). Importantly, R577 (a residue close to the kinase insertion region of the substrate molecule) contrib...

Embodiment 2

[0347] Example 2: In vitro tyrosine kinase activity of the R577E FGFR1 mutant.

[0348] To investigate the in vitro effects of the R577E mutant (FGFR1-RE), autophosphorylation assays were performed with wt-FGFR1 and the kinase domain of FGFR1-RE. with ATP and Mg at room temperature 2+ Purified FGFR1 kinase domains were incubated and monitored at various times by stopping the trans-autophosphorylation reaction with EDTA and running all samples on non-reducing native gels ( Figure 3A and Figure 3B ). Response profiles of wt-FGFR1 and FGFR1-RE on pristine gels clearly show that the trans autophosphorylation and reverse dephosphorylation responses of FGFR1-RE are significantly delayed compared to the wt-FGFR1 kinase domain. Trans autophosphorylation of the wt-FGFR1 kinase domain occurs within 10 min, reaching a fully phosphorylated state, which then undergoes reverse dephosphorylation. This is in contrast to FGFR1-RE, which becomes fully phosphorylated within 30 minutes and ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention provides moieties that bind to the asymmetric contact interface of a receptor tyrosine kinase (RTK), wherein the moieties inhibit ligand induced trans autophosphorylation of the RTK. The present invention also provides methods of treating or preventing an RTK-associated disease and methods for identifying moieties that bind to an asymmetric contact interface of an RTK.

Description

[0001] Cross References to Related Applications [0002] This application is related to and claims priority to US Provisional Application Serial No. 61 / 335,950, filed January 14, 2010, the entire contents of which are hereby incorporated by reference. [0003] Statement Regarding Government Sponsored Research or Development [0004] This invention was made with government support awarded by the National Institutes of Health under Contract Nos. R01-AR 051448, R01-AR 051886, P50 AR054086. The government may have certain rights in this invention. Background of the invention [0005] Ligand-induced tyrosine autophosphorylation plays an important role in controlling the activation of receptor tyrosine kinases (RTKs) and cell signaling (Schlessinger (1988) Trends Biochem. Sci., 3(11): 443-447 ; Schlessinger (2000) Cell, 103(2):211-225; Schlessinger and Lemmon (2003) Sci.STKE, 191:RE12; Schlessinger and Ullrich (1992) Neuron, 9(3):383-391; Lemmon and Schlessinger (1994) Trends Bio...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00C07K16/00
CPCG01N2500/04C07K14/71G01N33/573A61P19/08A61P35/00A61P43/00A61K48/00A61K38/18C07K16/00
Inventor J·H·贝I·莱克斯J·施莱斯英格
Owner YALE UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com