title: Therapeutic potential of targeting the oncogenic SHP2 phosphatase.
abstract: The Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase associated with various kinds of leukemia and solid tumors. Thus, there is substantial interest in developing SHP2 inhibitors as potential anticancer and antileukemia agents. Using a structure-guided and fragment-based library approach, we identified a novel hydroxyindole carboxylic acid-based SHP2 inhibitor 11a-1, with an IC50 value of 200 nM and greater than 5-fold selectivity against 20 mammalian PTPs. Structural and modeling studies reveal that the hydroxyindole carboxylic acid anchors the inhibitor to the SHP2 active site, while interactions of the oxalamide linker and the phenylthiophene tail with residues in the β5-β6 loop contribute to 11a-1's binding potency and selectivity. Evidence suggests that 11a-1 specifically attenuates the SHP2-dependent signaling inside the cell. Moreover, 11a-1 blocks growth factor mediated Erk1/2 and Akt activation and exhibits excellent antiproliferative activity in lung cancer and breast cancer as well as leukemia cell lines.
authors.affiliation: Department of Biochemistry and Molecular Biology, ‡Herman B. Wells Center for Pediatric Research, 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.forename: Ruo-Yu
authors.initials: RY
authors.lastname: Zhang
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Yu
authors.forename: Sijiu
authors.initials: S
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Gunawan
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Lane
authors.forename: Raghuveer S
authors.initials: RS
authors.lastname: Mali
authors.forename: Xingjun
authors.initials: X
authors.lastname: Li
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Chan
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.forename: Clark D
authors.initials: CD
authors.lastname: Wells
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D054852:Small Molecule Libraries; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11