RT Journal Article
SR Electronic
T1 Allosteric Non-competitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-cell Receptor Signals and Inflammation In Vivo
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.113.089847
DO 10.1124/mol.113.089847
A1 Michael Perron
A1 Shafinaz Chowdhury
A1 Isabelle Aubry
A1 Enrico Purisima
A1 Michel L. Tremblay
A1 H. Uri Saragovi
YR 2014
UL http://molpharm.aspetjournals.org/content/early/2014/01/28/mol.113.089847.abstract
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.