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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Area Under Curve
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Cell Line
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Cell Line, Tumor
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Cells, Cultured
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Female
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Humans
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Indoles / chemistry*
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Indoles / pharmacokinetics
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Indoles / pharmacology*
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Inhibitory Concentration 50
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Mice
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Mice, Inbred C57BL
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Mice, Nude
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Models, Chemical
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Models, Molecular
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Molecular Structure
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Mutation
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Neoplasms / metabolism
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Neoplasms / pathology
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Neoplasms / prevention & control
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Protein Binding
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Protein Structure, Tertiary
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / chemistry
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
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Salicylic Acid / chemistry*
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Small Molecule Libraries
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Triazoles / chemistry*
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Triazoles / pharmacokinetics
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Triazoles / pharmacology*
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Xenograft Model Antitumor Assays
Substances
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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
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Enzyme Inhibitors
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Indoles
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Small Molecule Libraries
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Triazoles
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Salicylic Acid