The structural basis for the selectivity of benzotriazole inhibitors of PTP1B.

Journal Article (Journal Article)

Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.

Full Text

Duke Authors

Cited Authors

  • Scapin, G; Patel, SB; Becker, JW; Wang, Q; Desponts, C; Waddleton, D; Skorey, K; Cromlish, W; Bayly, C; Therien, M; Gauthier, JY; Li, CS; Lau, CK; Ramachandran, C; Kennedy, BP; Asante-Appiah, E

Published Date

  • October 1, 2003

Published In

Volume / Issue

  • 42 / 39

Start / End Page

  • 11451 - 11459

PubMed ID

  • 14516196

Electronic International Standard Serial Number (EISSN)

  • 1520-4995

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi035098j


  • eng