Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics.
Article Details
- CitationCopy to clipboard
Combs AP, Yue EW, Bower M, Ala PJ, Wayland B, Douty B, Takvorian A, Polam P, Wasserman Z, Zhu W, Crawley ML, Pruitt J, Sparks R, Glass B, Modi D, McLaughlin E, Bostrom L, Li M, Galya L, Blom K, Hillman M, Gonneville L, Reid BG, Wei M, Becker-Pasha M, Klabe R, Huber R, Li Y, Hollis G, Burn TC, Wynn R, Liu P, Metcalf B
Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics.
J Med Chem. 2005 Oct 20;48(21):6544-8.
- PubMed ID
- 16220970 [ View in PubMed]
- Abstract
Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) ISOTHIAZOLIDINONE ANALOG Tyrosine-protein phosphatase non-receptor type 1 IC 50 (nM) 190 N/A N/A Details ISOTHIAZOLIDINONE ANALOG Tyrosine-protein phosphatase non-receptor type 1 IC 50 (nM) >100000 N/A N/A Details ISOTHIAZOLIDINONE ANALOG Tyrosine-protein phosphatase non-receptor type 1 Ki (nM) 180 N/A N/A Details N-ACETYL-L-PHENYLALANYL-4-[DIFLUORO(PHOSPHONO)METHYL]-L-PHENYLALANINAMIDE Tyrosine-protein phosphatase non-receptor type 1 IC 50 (nM) 1750 N/A N/A Details