title: Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Rongjun
authors.initials: R
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Ruo-Yu
authors.initials: RY
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Gunawan
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Lane
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine , 725 North Wolfe Street, Baltimore, Maryland 21205, United States.
authors.forename: Joong S
authors.initials: JS
authors.lastname: Shim
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Li-Fan
authors.initials: LF
authors.lastname: Zeng
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Yantao
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Lan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Clark D
authors.initials: CD
authors.lastname: Wells
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine , 725 North Wolfe Street, Baltimore, Maryland 21205, United States.
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States ; Department of Biochemistry and Molecular Biology and Chemical Genomics Core Facility, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
keywords: Protein tyrosine phosphatase; SHP2 inhibitors; anticancer agents; fragment-based library; pTyr mimetics