PT  - JOURNAL ARTICLE
AU  - Perron, Michael D.
AU  - Chowdhury, Shafinaz
AU  - Aubry, Isabelle
AU  - Purisima, Enrico
AU  - Tremblay, Michel L.
AU  - Saragovi, H. Uri
TI  - Allosteric Noncompetitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-Cell Receptor Signals and Inflammation In Vivo
AID  - 10.1124/mol.113.089847
DP  - 2014 Apr 01
TA  - Molecular Pharmacology
PG  - 553--563
VI  - 85
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/85/4/553.short
4100  - http://molpharm.aspetjournals.org/content/85/4/553.full
SO  - Mol Pharmacol2014 Apr 01; 85
AB  - CD45 is a receptor-like member of the protein tyrosine phosphatase (PTP) family. We screened in silico for small molecules binding at a predicted allosteric pocket unique to the CD45 intracellular domain, and validated inhibitors by in vitro phosphatase assays. Compound 211 exhibited a CD45 IC50 value of 200 nM and had >100-fold selectivity over six related PTPs. The relevance of the allosteric pocket was verified through site-directed mutagenesis. Compound 211 has a noncompetitive mechanism of action, and it is extremely effective at preventing dephosphorylation of substrate Lck phosphotyrosine (pY)-505 versus preventing dephosphorylation of Lck pY-393. In cultured primary T cells, compound 211 prevents T-cell receptor–mediated activation of Lck, Zap-70, and mitogen-activated protein kinase, and interleukin-2 production. In a delayed-type hypersensitivity reaction in vivo, compound 211 abolished inflammation. This work demonstrates a novel approach to develop effective allosteric inhibitors that can be expanded to target the corresponding allosteric domains of other receptor PTPs.