Abstract
Inhibitors of specific src homology 2 (SH2) domain binding interactions could potentially afford new therapeutic approaches toward a variety of diseases, including several cancers. To date SH2 domain inhibitors have been confined to small phosphotyrosyl (pTyr)-containing peptides that appear to bind along the surface of SH2 domains with specific recognition features protruding into the protein. Among these protrusions is the pTyr residue itself, which is inserted into a well-formed binding pocket. In the present study monomeric pTyr mimetics were prepared having key aspects of their structure constrained to conformations of the bound pTyr residue observed in the previously reported X-ray structure of a pTyr-peptide bound to the Lck SH2 domain. The resulting constrained pTyr mimetics were examined for inhibitory potency in six SH2 domain constructs: Lck, Src, Grb2, and the C-terminal SH2 domains of PLC gamma (PLC gamma-C) and the p85 subunit of PI-3 kinase (p85-C), as well as the N-terminal SH2 domain of SH PTP2. Although inhibition constants were in the millimolar range, it was observed that capping pTyr as its N alpha-acetyl carboxamide [(L)-1] provided a roughly 2-3-fold increase in potency relative to free pTyr. Diastereomer...Continue Reading
Citations
May 29, 2000·Chirality·S P BewS I Fukuzawa
Aug 1, 1997·Current Opinion in Biotechnology·T Kieber-EmmonsM I Greene
Sep 15, 2000·Bioorganic & Medicinal Chemistry Letters·J LeppänenT Järvinen
Aug 18, 1999·Bioorganic & Medicinal Chemistry Letters·G CaravattiP Furet
Mar 5, 2003·Bioorganic & Medicinal Chemistry·Frank J DekkerRob M J Liskamp
Oct 15, 2013·Chemical Reviews·Jacques RoudenJérôme Baudoux
Jan 13, 2009·Journal of the American Chemical Society·Sarvin MoghaddamMichael K Gilson
May 3, 2000·Journal of Hematotherapy & Stem Cell Research·S Sinha, S J Corey
Mar 1, 2006·International Journal of Peptide Research and Therapeutics·Terrence R Burke
Nov 4, 2010·The FEBS Journal·Denis PhichithBerangere Avalle
Nov 2, 1999·Journal of Molecular Biology·J M BradshawG Waksman
Jan 15, 2015·Chemical Communications : Chem Comm·Dorota Kowalczyk, Łukasz Albrecht
Aug 26, 2010·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Weiming XuYuping Zhang
Aug 7, 2009·Chemistry : a European Journal·Yadan WangRuyu Chen
Dec 17, 2009·Chemistry : a European Journal·Łukasz AlbrechtKarl Anker Jørgensen
Jun 18, 2003·Accounts of Chemical Research·Terrence R Burke, Kyeong Lee
Aug 26, 1998·Analytical Biochemistry·Y L Zhang, Z Y Zhang
Sep 20, 1996·Journal of Chromatography. B, Biomedical Applications·J A Boutin
Mar 12, 1999·Journal of Medicinal Chemistry·T R Lee, D S Lawrence
Oct 24, 2001·The Journal of Organic Chemistry·Dominique AlbouyGuita Etemad-Moghadam