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J Med Chem. 2005 Oct 20;48(21):6544-8.

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

Author information

1
Discovery Chemistry, Incyte Corporation, Experimental Station, E336/132A, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA. acombs@incyte.com

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.

PMID:
16220970
DOI:
10.1021/jm0504555
[Indexed for MEDLINE]

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