Tautomycetin Synthetic Analogues: Selective Inhibitors of Protein Phosphatase I.

Autor: Woydziak ZR; Department of Physical and Life Sciences, Nevada State College, 1300, Nevada State Dr., Henderson, NV 89002, USA., Yucel AJ; Department of Pharmaceutical Sciences, University of California, Irvine, 147 Biol. Sci. Admin., Irvine, CA 92697, USA., Chamberlin AR; Department of Pharmaceutical Sciences, University of California, Irvine, 147 Biol. Sci. Admin., Irvine, CA 92697, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2021 Mar 03; Vol. 16 (5), pp. 839-850. Date of Electronic Publication: 2020 Dec 10.
DOI: 10.1002/cmdc.202000801
Abstrakt: Ser/Thr protein phosphatases (PPs) regulate a substantial range of cellular processes with protein phosphatases 1 (PP1) and 2 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 <250 mM; seven possessed inhibition activity at 100 nM. The IC 50 values were determined for the seven most active analogues, which ranged from 34 to 1500 nM (PP1) and 70 to 6800 nM (PP2A). Four of the seven analogues possessed PP1 selectivity, and one demonstrated eightfold selectivity in the nanomolar range (PP1 IC 50 =34 nM, PP2A IC 50 =270 nM). A rationale is given for the observed differences in selectivity.
(© 2020 Wiley-VCH GmbH.)
Databáze: MEDLINE
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