PT  - JOURNAL ARTICLE
AU  - Michael Perron
AU  - Shafinaz Chowdhury
AU  - Isabelle Aubry
AU  - Enrico Purisima
AU  - Michel L. Tremblay
AU  - H. Uri Saragovi
TI  - Allosteric Non-competitive 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 Jan 28
TA  - Molecular Pharmacology
PG  - mol.113.089847
4099  - http://molpharm.aspetjournals.org/content/early/2014/01/28/mol.113.089847.short
4100  - http://molpharm.aspetjournals.org/content/early/2014/01/28/mol.113.089847.full
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. One compound 211 exhibited CD45 IC50 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 non-competitive mechanism of action, and it is extremely effective at preventing dephosphorylation of substrate Lck pY-505 versus preventing dephosphorylation of Lck pY-394. In cultured primary T cells, 211 prevents T-cell receptor-mediated activation of Lck, Zap-70 and MAPK, and IL-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.