Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment

A12 The SHP2 Inhibitor RMC-4630 in Patients with KRAS-Mutant Non-Small Cell Lung Cancer: Preliminary Evaluation of a First-in-Man Phase 1 Clinical Trial

(2020) S.I. Ou et al.   Journal of Thoracic Oncology

Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition

(2020) Jenny Y. Xue et al.   NATURE

Can the Help Match the Hype? KRASG12C-Specific Inhibitors and Beyond

(2020) Samuel J. Klempner et al.   Cancer Discovery

Resistance to allosteric SHP2 inhibition in FGFR-driven cancers through rapid feedback activation of FGFR

(2020) Hengyu Lu et al.   Oncotarget

Molecular mechanism of SHP2 activation by PD-1 stimulation

(2020) M. Marasco et al.   Science Advances

Allosteric inhibition of SHP2 stimulates anti-tumor immunity by transforming the immunosuppressive environment

(2020) Elsa Quintana et al.   CANCER RESEARCH

Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2

(2020) Ruo-Yu Zhang et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Discovery of SHP2-D26 as a First, Potent, and Effective PROTAC Degrader of SHP2 Protein

(2020) Mingliang Wang et al.   JOURNAL OF MEDICINAL CHEMISTRY

RAS-targeted therapies: is the undruggable drugged?

(2020) Amanda R. Moore et al.   NATURE REVIEWS DRUG DISCOVERY

Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR

(2020) Wupeng Yan et al.   Cell Reports

Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation

(2020) Guangya Zhu et al.   CELL

Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer

(2020) Matthew J. LaMarche et al.   JOURNAL OF MEDICINAL CHEMISTRY

SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-Dependent Tumors

(2019) Tamer A. Ahmed et al.   Cell Reports

Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors

(2019) Jeffrey T. Bagdanoff et al.   JOURNAL OF MEDICINAL CHEMISTRY

6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors

(2019) Patrick Sarver et al.   JOURNAL OF MEDICINAL CHEMISTRY

SHP2 inhibition overcomes RTK-mediated pathway re-activation in KRAS mutant tumors treated with MEK inhibitors

(2019) Hengyu Lu et al.   MOLECULAR CANCER THERAPEUTICS

KRASG12C inhibition produces a driver-limited state revealing collateral dependencies

(2019) Kevin Lou et al.   Science Signaling

Gain-of-Function SHP2 E76Q Mutant Rescuing Autoinhibition Mechanism Associated with Juvenile Myelomonocytic Leukemia

(2019) Ashfaq Ur Rehman et al.   Journal of Chemical Information and Modeling

Quantitative Interactomics in Primary T Cells Provides a Rationale for Concomitant PD-1 and BTLA Coinhibitor Blockade in Cancer Immunotherapy

(2019) Javier Celis-Gutierrez et al.   Cell Reports

Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition

(2019) Meagan B. Ryan et al.   CLINICAL CANCER RESEARCH

Dual Allosteric Inhibition of SHP2 Phosphatase

(2018) Michelle Fodor et al.   ACS Chemical Biology

Combination Cancer Therapy with Immune Checkpoint Blockade: Mechanisms and Strategies

(2018) Shetal A. Patel et al.   IMMUNITY

Selective inhibition of leukemia-associated SHP2E69K mutant by the allosteric SHP2 inhibitor SHP099

(2018) X Sun et al.   LEUKEMIA

Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase

(2018) Dietrich A. Ruess et al.   NATURE MEDICINE

Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition

(2018) Gabrielle S. Wong et al.   NATURE MEDICINE

SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo

(2018) Sara Mainardi et al.   NATURE MEDICINE

SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

(2018) Leila Dardaei et al.   NATURE MEDICINE

Understanding the tumor immune microenvironment (TIME) for effective therapy

(2018) Mikhail Binnewies et al.   NATURE MEDICINE

Shp-2 Is Dispensable for Establishing T Cell Exhaustion and for PD-1 Signaling In Vivo

(2018) Giorgia Rota et al.   Cell Reports

Large-Scale Phosphoproteomics Reveals Shp-2 Phosphatase-Dependent Regulators of Pdgf Receptor Signaling

(2018) Tanveer S. Batth et al.   Cell Reports

Off-target inhibition by active site-targeting SHP2 inhibitors

(2018) Ryouhei Tsutsumi et al.   FEBS Open Bio

RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers

(2018) Robert J. Nichols et al.   NATURE CELL BIOLOGY

SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models

(2018) Carmine Fedele et al.   Cancer Discovery

SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade

(2018) Mingxia Zhao et al.   Acta Pharmaceutica Sinica B

Phosphatases start shedding their stigma of undruggability

(2018) Asher Mullard   NATURE REVIEWS DRUG DISCOVERY

Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2

(2018) Ricardo A. P. Pádua et al.   Nature Communications

Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition

(2018) Jonathan R. LaRochelle et al.   Nature Communications

Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non–Small Cell Lung Cancer

(2017) Pasi A. Jänne et al.   JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION

Dabrafenib plus trametinib in patients with previously untreated BRAF V600E -mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial

(2017) David Planchard et al.   LANCET ONCOLOGY

Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS

(2017) Zhan Yao et al.   NATURE

The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1

(2017) Andrew A. Wylie et al.   NATURE

Affinity purification mass spectrometry analysis of PD-1 uncovers SAP as a new checkpoint inhibitor

(2017) Michael Peled et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition

(2017) Enfu Hui et al.   SCIENCE

Targeting ALK: Precision Medicine Takes on Drug Resistance

(2017) Jessica J. Lin et al.   Cancer Discovery

Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2

(2016) Jonathan R. LaRochelle et al.   BIOCHEMISTRY

Sticking It to Cancer with Molecular Glue for SHP2

(2016) Hao Ran et al.   CANCER CELL

Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

(2016) Jorge Garcia Fortanet et al.   JOURNAL OF MEDICINAL CHEMISTRY

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

(2016) Ying-Nan P. Chen et al.   NATURE

A framework for understanding and targeting residual disease in oncogene-driven solid cancers

(2016) Trever G Bivona et al.   NATURE MEDICINE

Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism

(2016) P. Lito et al.   SCIENCE

Selective Inhibitors of the Protein Tyrosine Phosphatase SHP2 Block Cellular Motility and Growth of Cancer Cells in vitro and in vivo

(2015) Stefanie Grosskopf et al.   ChemMedChem

Recent advances in RASopathies

(2015) Yoko Aoki et al.   JOURNAL OF HUMAN GENETICS

Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations

(2015) J. C. Hunter et al.   MOLECULAR CANCER RESEARCH

PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs

(2015) Anirudh Prahallad et al.   Cell Reports

The developing story of Sprouty and cancer

(2014) Samar Masoumi-Moghaddam et al.   CANCER AND METASTASIS REVIEWS

Loss of NF1 in Cutaneous Melanoma Is Associated with RAS Activation and MEK Dependence

(2014) Moriah H. Nissan et al.   CANCER RESEARCH

Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function

(2013) A. Mazharian et al.   BLOOD

Functional Redundancy of Sos1 and Sos2 for Lymphopoiesis and Organismal Homeostasis and Survival

(2013) Fernando C. Baltanás et al.   MOLECULAR AND CELLULAR BIOLOGY

NMR-based functional profiling of RASopathies and oncogenic RAS mutations

(2013) M. J. Smith et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2

(2013) Jie Sun et al.   Nature Communications

Essential role for Ptpn11 in survival of hematopoietic stem and progenitor cells

(2011) G. Chan et al.   BLOOD

Dynamic Substrate Enhancement for the Identification of Specific, Second-Site-Binding Fragments Targeting a Set of Protein Tyrosine Phosphatases

(2011) Marco F. Schmidt et al.   CHEMBIOCHEM

Sprouty-related Ena/Vasodilator-stimulated Phosphoprotein Homology 1-Domain-containing Protein (SPRED1), a Tyrosine-Protein Phosphatase Non-receptor Type 11 (SHP2) Substrate in the Ras/Extracellular Signal-regulated Kinase (ERK) Pathway

(2011) Martina Quintanar-Audelo et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

The tyrosine phosphatase Shp2 (PTPN11) in cancer

(2008) Gordon Chan et al.   CANCER AND METASTASIS REVIEWS

The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway

(2007) Marie Dance et al.   CELLULAR SIGNALLING