Tautomycetin Synthetic Analogues: Selective Inhibitors of Protein Phosphatase I.
ChemMedChem
; 16(5): 839-850, 2021 03 03.
Article
in En
| MEDLINE
| ID: mdl-33301228
ABSTRACT
Ser/Thr protein phosphatases (PPs) regulate a substantial range of cellular processes with protein phosphatases 1 (PP1) and 2â
A (PP2A) accounting for over 90 % of the activity within cells. Nevertheless, tools to study PPs are limited as PPs inhibitors, particularly those selective for PP1 inhibition, are relatively scarce. Two examples of PP1-selective inhibitors, which share structural similarities, are tautomycin (TTM) and tautomycetin (TTN). This work describes the development of PP1/PP2A inhibitors that incorporate key structural features of TTM and TTN and are designed to conserve regions known to bind the active site of PP1/PP2A but vary regions that differentially contact the hydrophobic groove of PP1/PP2A. In all 28 TTN analogues were synthetically generated that inhibit PP1/PP2A activity at <250â
mM; seven possessed inhibition activity at 100â
nM. The IC50 values were determined for the seven most active analogues, which ranged from 34 to 1500â
nM (PP1) and 70 to 6800â
nM (PP2A). Four of the seven analogues possessed PP1 selectivity, and one demonstrated eightfold selectivity in the nanomolar range (PP1 IC50 =34â
nM, PP2A IC50 =270â
nM). A rationale is given for the observed differences in selectivity.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Neuropeptide Y
/
Enzyme Inhibitors
/
Protein Phosphatase 2
/
Furans
/
Lipids
Limits:
Humans
Language:
En
Journal:
ChemMedChem
Year:
2021
Document type:
Article