ArticleNature2016
Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.
Article in Nature, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 508 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
508 citing papers in PubMed.
- Binimetinib and encorafenib for the treatment of advanced solid tumors with non-V600E BRAF mutations: results from the Phase II BEAVER trial.Nature communications · 2026Trial
- BGC1201: A potent allosteric SHP2 inhibitor with broad antitumor activity in lung, pancreatic, and esophageal cancer xenografts.Pharmaceutical science advances · 2026Article
- Recent Advances in Research on SHP Family Phosphatases: Signal Regulation Mechanisms and Disease Associations.Cell biochemistry and function · 2026Review
- Inhibition of SHP2 enhances the effects of selective receptor tyrosine kinase inhibitors in untreated preclinical models of RET-mutated thyroid cancer.Investigational new drugs · 2026Article
- Temporal transcriptomic profiling uncovers multilevel suppression of RANKL-driven osteoclast differentiation by 14-3-3ζ.The Journal of biological chemistry · 2026Article
- Alterations of the host-lung microbiome metasystem in systemic inflammatory response syndrome is associated with secondary pneumonia.Cell reports. Medicine · 2026Article
- Dynamic view of an allosteric intermediate in a positively cooperative dimer.bioRxiv : the preprint server for biology · 2026Article
- Discovery of a covalent FGFR2-selective inhibitor overcoming clinically-acquired resistance mutations.Nature communications · 2026Article
- A Potent and Selective Quinolone-Based PTPN22 Inhibitor with Improved Immunotherapeutic Activity.Journal of medicinal chemistry · 2026Article
- Drug Discovery of Allosteric Molecular Glue Degraders (aMGDs): Expanding the Landscape of Targeted Protein Degradation.Journal of medicinal chemistry · 2026Article
- Molecular Mechanisms and Targeted Therapies of PTPN2 in Metabolic Diseases: A Review.Biomolecules · 2026Review
- Context-dependent synthetic lethality - an emerging precision therapeutic approach.Nature reviews. Cancer · 2026Review
- SHP2 as a pivotal modulator of the tumor microenvironment in gastrointestinal cancers: from mechanisms to targeted therapies.Journal of translational medicine · 2026Review
- Probing 3-Amino-2H-Azaindazoles as Allosteric Inhibitors of the Protein Tyrosine Phosphatase SHP2.ChemMedChem · 2026Article
- Targeting frizzled receptors (FZDs) for anti-tumor therapy: From orthosteric to allosteric inhibition.Acta pharmaceutica Sinica. B · 2026Review
- Multiplexed single-cell transcriptomics reveals diverse phenotypic outcomes for pathogenic SHP2 variants.Science advances · 2026Article
- Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models.Journal of medicinal chemistry · 2026Article
- Posttranslational modifications remodel proteome-wide ligandability.Nature chemical biology · 2026Article
- High-throughput biochemical phenotyping of SHP2 variants reveals the molecular basis of diseases and allosteric drug inhibition.bioRxiv : the preprint server for biology · 2026Article
- Mapping the SHP2 Allosteric Pocket With Target-Biased Covalent Fragments.Chembiochem : a European journal of chemical biology · 2026Article
448 more citing papers are in PubMed but not listed here.
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Authors and funding
53 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.