Redox-stable, non-phosphorylated cyclic peptide inhibitors of SH2 domain binding to target protein, conjugates thereof, compositions and methods of synthesis and use

US6951915B2 · kind B2 · utility

Assignees

• The United States of America, as represented by the Department of Health and Human Services · US
• Georgetown University · US

Inventors

• Peter P. Roller · Rockville, US
• Ya-Qiu Long · Bethesda, US
• Feng-Di Lung · Taichung, TW
• C. Richter King · Washington, US
• Dajun Yang · Suzhou, CN

Key dates

• Filing date: Nov 30, 2001
• Grant date: Oct 4, 2005
• Expiry date: Dec 11, 2022

Classification

• Technology area (CPC A): Human Necessities
• CPC primary: A61K38/00
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

A compound of formula: in which L is sulfur, sulfoxide, oxygen or methylene, and a compound of formula: in which (i) aa1 is Adi and aa4 is Glu or (ii) each of aa1 and aa4 is Adi, L is sulfur, sulfoxide, oxygen or methylene, which compounds (and their conjugates) bind to an SH2 domain in a protein comprising an SH2 domain, are non-phosphorylated, are redox-stable in vivo, are characterized by an IC50 in vivo of less than about 4.0 μM with respect to the SH2 domain in Grb2, and, upon binding to the SH2 domain of Grb2, have a turn conformation. A conjugate comprising a compound as described above and a carrier agent, a composition comprising (i) a compound or a conjugate as described above and (ii) a carrier, a method of inhibiting binding of an SH2 domain in a protein comprising an SH2 domain to a target protein in an animal, wherein the SH2 domain is contacted with a target protein-binding inhibiting effective amount of a compound or a conjugate as described above, and a method of synthesizing such conjugates.