Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design (Q38911598)

7 September 2017

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title

Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design (English)

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7 September 2017

Jonathan M L Ostrem

1

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7 September 2017

Kevan M Shokat

series ordinal

2

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7 September 2017

language of work or name

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29 July 2016

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Nature Reviews Drug Discovery

7 September 2017

published in

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7 September 2017

volume

15

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7 September 2017

issue

11

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7 September 2017

page(s)

771-785

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The Son of sevenless Gene Product: a Putative Activator of Ras

7 September 2017

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RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs

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A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants

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The neurofibromatosis type 1 gene encodes a protein related to GAP

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ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK

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Activation of the MAP kinase pathway by the protein kinase raf

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Mammalian Ras interacts directly with the serine/threonine kinase Raf

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Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase

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Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro

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Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1

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Association of p21ras with phosphatidylinositol 3-kinase

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Phosphatidylinositol-3-OH kinase as a direct target of Ras

31 March 2020

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The activation of phosphatidylinositol 3-kinase by Ras

31 March 2020

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Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002.

31 March 2020

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Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator

31 March 2020

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Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap

31 March 2020

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ralGDS family members interact with the effector loop of ras p21.

31 March 2020

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A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation

31 March 2020

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p21ras is modified by a farnesyl isoprenoid

31 March 2020

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K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors

31 March 2020

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A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane

31 March 2020

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Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins

31 March 2020

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A dimerization-dependent mechanism drives RAF catalytic activation

31 March 2020

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H-Ras forms dimers on membrane surfaces via a protein-protein interface.

31 March 2020

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GTP-Dependent K-Ras Dimerization

31 March 2020

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Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway

31 March 2020

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https://api.crossref.org/works/10.1038%2FNRD.2016.139

Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene

31 March 2020

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https://api.crossref.org/works/10.1038%2FNRD.2016.139

T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes

31 March 2020

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https://api.crossref.org/works/10.1038%2FNRD.2016.139

Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses

31 March 2020

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https://api.crossref.org/works/10.1038%2FNRD.2016.139

Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

A comprehensive survey of Ras mutations in cancer

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Analysis of the transforming potential of the human H-ras gene by random mutagenesis

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Mutational and kinetic analyses of the GTPase-activating protein (GAP)-p21 interaction: the C-terminal domain of GAP is not sufficient for full activity

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Allosteric modulation of Ras positions Q61 for a direct role in catalysis

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

NMR-based functional profiling of RASopathies and oncogenic RAS mutations.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Biological properties of human c-Ha-ras1 genes mutated at codon 12.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

K-ras is an essential gene in the mouse with partial functional overlap with N-ras

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Wildtype Kras2 can inhibit lung carcinogenesis in mice

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

A requirement for wild-type Ras isoforms in mutant KRas-driven signalling and transformation

31 March 2020

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https://api.crossref.org/works/10.1038%2FNRD.2016.139

Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Loss of wild-type Kras promotes activation of all Ras isoforms in oncogenic Kras-induced leukemogenesis.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Chemical genetics: where genetics and pharmacology meet

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Three-dimensional structure of an oncogene protein: catalytic domain of human c-H-ras p21.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Crystal structures at 2.2 A resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with GDP

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Solution structure and dynamics of ras p21.GDP determined by heteronuclear three- and four-dimensional NMR spectroscopy

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Mapping the nucleotide and isoform-dependent structural and dynamical features of Ras proteins

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Dynamic properties of the Ras switch I region and its importance for binding to effectors

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Structure of the G60A mutant of Ras: implications for the dominant negative effect

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Structural Basis for Conformational Dynamics of GTP-bound Ras Protein

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Solution structure of the state 1 conformer of GTP-bound H-Ras protein and distinct dynamic properties between the state 1 and state 2 conformers

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Mutagenesis of the H-ras p21 at glycine-60 residue disrupts GTP-induced conformational change

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Ras interaction with two distinct binding domains in Raf-1 may be required for Ras transformation

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Dominant inhibitory mutations in the Mg(2+)-binding site of RasH prevent its activation by GTP

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

The Ras mutant D119N is both dominant negative and activated

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Defective K-Ras oncoproteins overcome impaired effector activation to initiate leukemia in vivo

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Requirement for interaction of PI3-kinase p110α with RAS in lung tumor maintenance

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Characterization of a Ras mutant with identical GDP- and GTP-bound structures

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Physiological concentrations of purines and pyrimidines

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Oncogenic K-Ras requires activation for enhanced activity

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

EGF receptor is required for KRAS-induced pancreatic tumorigenesis

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

K-ras mutations and benefit from cetuximab in advanced colorectal cancer.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

A novel Galphaq/11-selective inhibitor

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Reaching for high-hanging fruit in drug discovery at protein-protein interfaces

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Brefeldin A acts to stabilize an abortive ARF-GDP-Sec7 domain protein complex: involvement of specific residues of the Sec7 domain

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Farnesol modification of Kirsten-ras exon 4B protein is essential for transformation

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Development of farnesyl transferase inhibitors: a review

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Farnesyltransferase inhibitors: a detailed chemical view on an elusive biological problem

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Ras oncoprotein inhibitors: the discovery of potent, ras nucleotide exchange inhibitors and the structural determination of a drug-protein complex

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

An orthosteric inhibitor of the Ras-Sos interaction

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Detection and structural characterization of ras oncoprotein-inhibitors complexes by electrospray mass spectrometry

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Interaction of a novel GDP exchange inhibitor with the Ras protein

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Activation of ras p21 transforming properties associated with an increase in the release rate of bound guanine nucleotide

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Neutralizing monoclonal antibody against ras oncogene product p21 which impairs guanine nucleotide exchange

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Design and characterization of a new class of inhibitors of ras activation

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-Ras(G13D).

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Stabilizing the pro-apoptotic BimBH3 helix (BimSAHB) does not necessarily enhance affinity or biological activity

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Germline gain-of-function mutations in SOS1 cause Noonan syndrome

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Structural evidence for feedback activation by Ras.GTP of the Ras-specific nucleotide exchange factor SOS

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

The structural basis of the activation of Ras by Sos

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Structural analysis of autoinhibition in the Ras activator Son of sevenless

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Thrombomodulin tightens the thrombin active site loops to promote protein C activation

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Sulindac sulfide inhibits Ras signaling

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Identification of potent Ras signaling inhibitors by pathway-selective phenotype-based screening

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Sulindac-derived Ras pathway inhibitors target the Ras-Raf interaction and downstream effectors in the Ras pathway

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c-Raf interaction and activation of MAP kinase phosphatases

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Inhibitors of Ras/Raf-1 interaction identified by two-hybrid screening revert Ras-dependent transformation phenotypes in human cancer cells.

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Genetic and functional characterization of putative Ras/Raf interaction inhibitors in C. elegans and mammalian cells

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Design and synthesis of a transferable farnesyl pyrophosphate analogue to Ras by protein farnesyltransferase

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Identification of pyrazolopyridazinones as PDEδ inhibitors

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Dragging ras back in the ring

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

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

31 March 2020

1 reference

https://api.crossref.org/works/10.1038%2FNRD.2016.139

Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation

31 March 2020

1 reference

12 December 2020

The role of EGF-related peptides in tumor growth.

1 reference

12 December 2020

Asparagine 26, glutamic acid 31, valine 45, and tyrosine 64 of Ras proteins are required for their oncogenicity

1 reference

12 December 2020

Mutations that abolish the ability of Ha-Ras to associate with Raf-1

1 reference

12 December 2020

Kinetic and structural analysis of the Mg(2+)-binding site of the guanine nucleotide-binding protein p21H-ras

1 reference

12 December 2020

Biochemical properties of Ha-ras encoded p21 mutants and mechanism of the autophosphorylation reaction

1 reference

12 December 2020

Different structural requirements within the switch II region of the Ras protein for interactions with specific downstream targets

1 reference

12 December 2020

Post-translational processing of p21ras is two-step and involves carboxyl-methylation and carboxy-terminal proteolysis

1 reference

12 December 2020

Identifiers

DOI

10.1038/NRD.2016.139

1 reference

7 September 2017

1 reference