Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors

Rongjun He, Zhi Hong Yu, Ruo Yu Zhang, Li Wu, Andrea M. Gunawan, Brandon S. Lane, Joong S. Shim, Li Fan Zeng, Yantao He, Lan Chen, Clark D. Wells, Jun O. Liu, Zhong Yin Zhang

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Protein tyrosine phosphatases (PTPs) are potential therapeutic targets for many diseases. Unfortunately, despite considerable drug discovery efforts devoted to PTPs, obtaining selective and cell permeable PTP inhibitors remains highly challenging. We describe a strategy to explore the existing drug space for previously unknown PTP inhibitory activities. This led to the discovery of cefsulodin as an inhibitor of SHP2, an oncogenic phosphatase in the PTP family. Crystal structure analysis of SHP2 interaction with cefsulodin identified sulfophenyl acetic amide (SPAA) as a novel phosphotyrosine (pTyr) mimetic. A structure-guided and SPAA fragment-based focused library approach produced several potent and selective SHP2 inhibitors. Notably, these inhibitors blocked SHP2-mediated signaling events and proliferation in several cancer cell lines. Thus, SPAA may serve as a new platform for developing chemical probes for other PTPs.

Original languageEnglish (US)
Pages (from-to)782-786
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume6
Issue number7
DOIs
StatePublished - Jul 9 2015

    Fingerprint

Keywords

  • anticancer agents
  • fragment-based library
  • Protein tyrosine phosphatase
  • pTyr mimetics
  • SHP2 inhibitors

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

He, R., Yu, Z. H., Zhang, R. Y., Wu, L., Gunawan, A. M., Lane, B. S., Shim, J. S., Zeng, L. F., He, Y., Chen, L., Wells, C. D., Liu, J. O., & Zhang, Z. Y. (2015). Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors. ACS Medicinal Chemistry Letters, 6(7), 782-786. https://doi.org/10.1021/acsmedchemlett.5b00118