Ya-Qiu Long

Significant compensatory role of position Y-2 conferring high affinity to non-phosphorylated inhibitors of GRB2-SH2 domain

Systematic modification of amino acid at position Y-2 of a library-derived non-phosporylated thioether-cyclized peptide, cyclo(CH2CO-Glu2-Leu-Tyr0-Glu-Asn-Val-Gly-Met-Tyr-Cys) -amide, aided by molecular modeling, demonstrates that the Glu(-2) sidechain compensates for the absence of Tyr0 phosphorylation in retaining effective binding to Grb2-SH2 domain. Replacement of Glu(-2) with gamma-carboxyglutamic acid produced a high affinity inhibitor, the first example with submicromolar affinity (IC50 = 640 nM).

Potent Grb2–SH2 domain antagonists not relying on phosphotyrosine mimics

Development of Grb2-SH2 domain antagonists is an effective approach to inhibit the growth of malignant cells by modulating Grb2-related Ras signaling. We report here potent Grb2-SH2 domain antagonists that do not rely on phosphotyrosine or its mimics. These non-phosphorylated antagonists were developed and further modified by constraining the backbone conformation and optimizing amino acid side chains of a phage library-derived peptide, G1TE. After extensive SAR studies and structural optimization, non-phosphorylated peptide 12 was discovered with an IC(50) of 75 nM. This potent peptidomimetic provides a novel template for the development of non-pTyr containing Grb2-SH2 domain antagonists and acts as a chemotherapeutic lead for the treatment of erbB2-related cancer.

Bicyclic Peptide Inhibitors of an Epithelial Cell-Derived Transmembrane Protease, Matriptase

Matriptase is a recently identified type II transmembrane protease that is found on the surface of epithelial cells [1,2]. It is overexpressed in most cancer cells, including human breast cancer cells. It is a multidomain protein with a C-terminal extracellular region containing the protease domain. It activates urokinase-type of plasminogen activator (uPA), and the protease activated receptor (Par-2). It has been demonstrated that matriptase can proteolytically activate hepatocyte growth factor (HGF/Scatter Factor) to its active form, and thus it may function in epithelial cell migration, cancer invasion and metastasis [2]. Developing inhibitors of matriptase provides for a therapeutic approach to metastatic diseases, and in particular, cancer.