Acquisition of a potent and selective TC-PTP inhibitor via a stepwise fluorophore-tagged combinatorial synthesis and screening strategy

Sheng Zhang, Lan Chen, Yong Luo, Andrea Gunawan, David S. Lawrence, Zhong-Yin Zhang

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Protein tyrosine phosphatases (PTPs) regulate a broad range of cellular processes including proliferation, differentiation, migration, apoptosis, and immune responses. Dysfunction of PTP activity is associated with cancers, metabolic syndromes, and autoimmune disorders. Consequently, small molecule PTP inhibitors should serve not only as powerful tools to delineate the physiological roles of these enzymes in vivo but also as lead compounds for therapeutic development. We describe a novel stepwise fluorophoretagged combinatorial library synthesis and competitive fluorescence polarization screening approach that transforms a weak and general PTP inhibitor into an extremely potent and selective TC-PTP inhibitor with highly efficacious cellular activity. The result serves as a proof-of-concept in PTP inhibitor development, as it demonstrates the feasibility of acquiring potent, yet highly selective, cell permeable PTP inhibitory agents. Given the general nature of the approach, this strategy should be applicable to other PTP targets.

Original languageEnglish
Pages (from-to)13072-13079
Number of pages8
JournalJournal of the American Chemical Society
Volume131
Issue number36
DOIs
StatePublished - Sep 16 2009

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Protein Tyrosine Phosphatases
Fluorophores
Phosphatases
Screening
Proteins
Lead compounds
Fluorescence Polarization
Cell death
Enzymes
Fluorescence
Polarization
Apoptosis
Molecules

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Acquisition of a potent and selective TC-PTP inhibitor via a stepwise fluorophore-tagged combinatorial synthesis and screening strategy. / Zhang, Sheng; Chen, Lan; Luo, Yong; Gunawan, Andrea; Lawrence, David S.; Zhang, Zhong-Yin.

In: Journal of the American Chemical Society, Vol. 131, No. 36, 16.09.2009, p. 13072-13079.

Research output: Contribution to journalArticle

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