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Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhi

Journal Article · · J. Med. Chem.
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Research Organization:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Organization:
DOE - Office Of Science; INDUSTRY
OSTI ID:
1900762
Journal Information:
J. Med. Chem., Journal Name: J. Med. Chem. Journal Issue: (14) Vol. 65
Country of Publication:
United States
Language:
ENGLISH

References (40)

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Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS journal August 2018
Small Molecule Binding Sites on the Ras:SOS Complex Can Be Exploited for Inhibition of Ras Activation journal February 2015
Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery journal August 2019
One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS journal March 2021
SOS GEFs in health and disease journal December 2020
Noonan syndrome patient-specific induced cardiomyocyte model carrying SOS1 gene variant c.1654A>G journal March 2021
Structural Evidence for Feedback Activation by Ras·GTP of the Ras-Specific Nucleotide Exchange Factor SOS journal March 2003
Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling journal June 2018
KRYSTAL-1: Updated activity and safety of adagrasib (MRTX849) in patients (Pts) with unresectable or metastatic pancreatic cancer (PDAC) and other gastrointestinal (GI) tumors harboring a KRASG12C mutation. journal February 2022
Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis journal January 2012
Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction journal January 2019
Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange journal February 2014
A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy journal June 2020
Oncogenic Signaling Pathways in The Cancer Genome Atlas journal April 2018
Sotorasib for Lung Cancers with KRAS p.G12C Mutation journal June 2021
Small Molecule–Mediated Activation of RAS Elicits Biphasic Modulation of Phospho-ERK Levels that Are Regulated through Negative Feedback on SOS1 journal February 2018
Frequency and outcomes of brain metastases in patients withHER2‐mutant lung cancers journal August 2019
Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2 journal October 1996
Germline gain-of-function mutations in SOS1 cause Noonan syndrome journal December 2006
Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS journal May 2018
High-throughput screening identifies small molecules that bind to the RAS:SOS:RAS complex and perturb RAS signaling journal May 2018
Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome journal December 2006
Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations journal March 2022
Mammalian Son of Sevenless Guanine Nucleotide Exchange Factors: Old Concepts and New Perspectives journal March 2011
Decreased GTPase activity of K- ras mutants deriving from human functional adrenocortical tumours journal March 2000
Identification of the Clinical Development Candidate MRTX849 , a Covalent KRAS G12C Inhibitor for the Treatment of Cancer journal April 2020
A Mutation in the SOS1 Gene Causes Hereditary Gingival Fibromatosis Type 1 journal April 2002
Frequency of brain metastases and outcomes in patients with HER2-, KRAS-, and EGFR-mutant lung cancers. journal May 2018
First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1) journal August 2022
RAS Proteins and Their Regulators in Human Disease journal June 2017
Small Molecule SOS1 Agonists Modulate MAPK and PI3K Signaling via Independent Cellular Responses journal February 2019
Breaking Oncogene Addiction: Getting RTK/RAS-Mutated Cancers off the SOS journal May 2021
CSF as a Surrogate for Assessing CNS Exposure: An Industrial Perspective journal January 2008
Targeting Son of Sevenless 1: The pacemaker of KRAS journal June 2021
BI-3406, a Potent and Selective SOS1–KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition journal January 2021
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Germ Line Gain of Function with SOS1 Mutation in Hereditary Gingival Fibromatosis journal May 2007
The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants journal July 1997

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