Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics.

Article Details

Citation

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
DrugTargetPropertyMeasurementpHTemperature (°C)
ISOTHIAZOLIDINONE ANALOGTyrosine-protein phosphatase non-receptor type 1IC 50 (nM)190N/AN/ADetails
ISOTHIAZOLIDINONE ANALOGTyrosine-protein phosphatase non-receptor type 1IC 50 (nM)>100000N/AN/ADetails
ISOTHIAZOLIDINONE ANALOGTyrosine-protein phosphatase non-receptor type 1Ki (nM)180N/AN/ADetails
N-ACETYL-L-PHENYLALANYL-4-[DIFLUORO(PHOSPHONO)METHYL]-L-PHENYLALANINAMIDETyrosine-protein phosphatase non-receptor type 1IC 50 (nM)1750N/AN/ADetails