Protein tyrosine phosphatases: strategies for distinguishing proteins in a family containing multiple drug targets and anti-targets.
PTP1B, but also proteins that are essential to cell development and survival. The availability of sequences and representative structures for the PTP family allows better identification of anti-targets, closely related family members likely to cross-react with directed inhibitors. Eight PTP subfamilies, classified by active site information and overall PTP catalytic domain structure similarity, are reviewed here: 1) the tyrosine-specific PTPs, 2) the dual-specificity PTPs, 3) the cdc25 subclass; 4) the Pten subclass; 5) the myotubularins, 6) the PRL subclass, 7) the low molecular weight PTPs, and 8) the newly defined cdc14 subclass. PTP subfamily classification and structure information can be incorporated into design strategies aimed at identifying potent and selective small molecule inhibitors. The accumulating inhibition data for compounds screened against panels of PTPs is reviewed. The in vitro data can yield clues to specificity so that individual subfamilies can be matched with effective scaffolds to jumpstart lead design and reduce false starts.
Hoffman
Brian T
BT
Cengent Therapeutics, 10929 Technology Place, San Diego, CA 92127, USA. info@cengent.com
Nelson
Melanie R
MR
Burdick
Keith
K
Baxter
Susan M
SM
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D017027:Protein Tyrosine Phosphatases