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 journalArticlepeer-review

26 Scopus citations


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
Issue number7
StatePublished - Jul 9 2015


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

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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