Description of Invention:
The present invention provides for ultra-potent Grb2 SH2 domain-binding compounds, or a pharmaceutically acceptable salt thereof. The compounds of the present invention represent tetrapeptide mimetics whose conformation is constrained through macrocyclization. Low picomolar binding affinity is achieved in in vitro Grb2 SH2 domain binding assays. Addition of the covered agent to the extracellular media of erbB-2 over-expressing breast cancer cells at low nanomolar concentrations results in effective intracellular blockade of Grb2 association with activated cytoplasmic erbB-2 tyrosine kinase. Antimitogenic effects are observed in erbB-2-dependent breast cancer cells in culture at sub-micromolar concentrations. The present invention further provides a pharmaceutical composition comprising a pharmaceutically or pharmacologically acceptable carrier and a compound of the present invention. The present invention also provides a method for inhibiting an SH2 domain from binding with a phosphoproteins comprising contacting an SH2 domain with a compound of the present invention. The present invention also provides a method of preventing or treating a disease, state, or condition by the use of the compound. While the invention has been described and disclosed below in connection with certain embodiments and procedures, it is not intended to limit the invention to those specific embodiments. Rather it is intended to cover all such alternative embodiments and modifications as fall within the spirit and scope of the invention.
Patent Status:
DHHS Reference No. E-315-2003/0 --
U.S. Provisional Application No. 60/504,241 filed 18 Sep 2003
U.S. Patent Application No. 10/944,699 filed 17 Sep 2004
U.S. Patent Application No. 11/932,424 filed 31 Oct 2007
Relevant Publication:
Z Shi et al. A novel macrocyclic tetrapeptide mimetic that exhibits low-picomolar Grb2 SH2 domain-binding affinity. Biochem Biophys Res Commun. 2003 Oct 17;310(2):378-383. [PubMed abs]
Z Shi et al. Synthesis of a 5-methylindolyl-containing macrocycle that displays ultrapotent Grb2 SH2 domain-binding affinity. J Med Chem. 2004 Feb 12;47(4):788-791. [PubMed abs]
Portfolios: Cancer
Cancer -Therapeutics-Biological Response Modifiers-Other Cancer -Therapeutics
For Additional Information Please Contact: Adaku Nwachukwu J.D.
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: 301 435-5560
Email: madua@mail.nih.gov
Fax: 301 402-0220
