title: Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2).
abstract: The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with Noonan syndrome, various kinds of leukemias, and solid tumors. Thus, there is considerable interest in SHP2 as a potential target for anticancer and antileukemia therapy. We report a salicylic acid based combinatorial library approach aimed at binding both active site and unique nearby subpockets for enhanced affinity and selectivity. Screening of the library led to the identification of a SHP2 inhibitor II-B08 (compound 9) with highly efficacious cellular activity. Compound 9 blocks growth factor stimulated ERK1/2 activation and hematopoietic progenitor proliferation, providing supporting evidence that chemical inhibition of SHP2 may be therapeutically useful for anticancer and antileukemia treatment. X-ray crystallographic analysis of the structure of SHP2 in complex with 9 reveals molecular determinants that can be exploited for the acquisition of more potent and selective SHP2 inhibitors.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.forename: Yantao
authors.initials: Y
authors.lastname: He
authors.forename: Sijiu
authors.initials: S
authors.lastname: Liu
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yu
authors.forename: Zhong-Xing
authors.initials: ZX
authors.lastname: Jiang
authors.forename: Zhenyun
authors.initials: Z
authors.lastname: Yang
authors.forename: Yuanshu
authors.initials: Y
authors.lastname: Dong
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Nabinger
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Gunawan
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Chan
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D020156:Salicylic Acid / Q000737:chemistry*; D054852:Small Molecule Libraries; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C549053:3-(1-(3-(biphenyl-4-ylamino)-3-oxopropyl)-1H-1,2,3-triazol-4-yl)-6-hydroxy-1-methyl-2-phenyl-1H-indole-5-carboxylic acid; D004791:Enzyme Inhibitors; D007211:Indoles; D054852:Small Molecule Libraries; D014230:Triazoles; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D020156:Salicylic Acid