A5004053040- Melanoma and MAPK Pathways
- Cancer Mechanisms and Therapy
- ATP Synthase and ATPases Research
- Biochemical and Molecular Research
- Cytokine Signaling Pathways and Interactions
- Protein Kinase Regulation and GTPase Signaling
- Advanced Breast Cancer Therapies
- Colorectal Cancer Treatments and Studies
- Protein Tyrosine Phosphatases
- Computational Drug Discovery Methods
- Cell Adhesion Molecules Research
- Synthesis and biological activity
- PI3K/AKT/mTOR signaling in cancer
- Enzyme Structure and Function
- Synthesis of Tetrazole Derivatives
- Ubiquitin and proteasome pathways
- NF-κB Signaling Pathways
- Blood properties and coagulation
- Biotin and Related Studies
- X-ray Diffraction in Crystallography
- S100 Proteins and Annexins
- Cellular Mechanics and Interactions
- Bioinformatics and Genomic Networks
- Protein Degradation and Inhibitors
- Cancer-related Molecular Pathways
Genomics Institute of the Novartis Research Foundation
2017-2024
Mirati Therapeutics (United States)
2022-2023
Genentech
2014
University of California, San Diego
2007-2010
Cornell University
2007
University of Virginia
2007
SOS1 is one of the major guanine nucleotide exchange factors that regulates ability KRAS to cycle through its "on" and "off" states. Disrupting SOS1:KRASG12C protein-protein interaction (PPI) can increase proportion GDP-loaded KRASG12C, providing a strong mechanistic rationale for combining inhibitors SOS1:KRAS complex with like MRTX849 target KRASG12C. In this report, we detail design discovery MRTX0902─a potent, selective, brain-penetrant, orally bioavailable binder disrupts PPI. Oral...
Integrins are large membrane-spanning receptors fundamental to cell adhesion and migration. Integrin adhesiveness for the extracellular matrix is activated by cytoskeletal protein talin via direct binding of its phosphotyrosine-binding-like F3 domain cytoplasmic tail beta integrin subunit. The phosphotyrosine-binding signaling Dok1, on other hand, has an inactivating effect integrins, a phenomenon that modulated tyrosine phosphorylation. Using full-length tyrosine-phosphorylated...
KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of RTK/MAPK pathway. The Son Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for RAS subfamily small GTPases represents druggable target Using structure-based drug discovery approach, MRTX0902 was identified selective potent SOS1 inhibitor that disrupts KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated on translates...
RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase KRAS mutant tumors has established genetically engineered mouse models and tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective cellular potent inhibitors remain challenging identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as their preparation . WO 2014151616, 2014...
Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by activated BRAF oncogene. Here, we report antitumor properties of RAF709, a novel ATP-competitive kinase with high potency and selectivity against kinases. RAF709 exhibited mode inhibition distinct from monomer inhibitors such as vemurafenib, showing equal activity both monomers dimers. As result, inhibited MAPK signaling tumor models harboring either BRAFV600 alterations or mutant N- KRAS-driven signaling,...
Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due the complex nature RAF signaling, downstream activated RAS, poor overall kinase selectivity putative inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C inhibitor, which was developed by focusing on drug-like properties selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; J. Med. Chem.2017, 60,...
We used a TAP-tag approach to identify candidate binding proteins for the related Ras family GTPases: H-Ras, R-Ras, and Rap1A. Protein complexes were isolated from mouse fibroblasts, component identified by combination of nanoflow HPLC tandem mass spectrometry. H-Ras was found associate with numerous cytoskeletal including talin-1. R-Ras Rap1A each associated various signaling molecules, many which are membrane-associated. Thus, we have established first database potential interactors in...
Dynamic signals linking the actin cytoskeleton and cell adhesion receptors are essential for morphogenesis during development normal tissue homeostasis. Abi1 is a central regulator of polymerization through interactions with multiple protein complexes. However, in vivo role remains to be defined. The α4 integrin receptor associated enhanced protrusive activity regulation directional migration. Among subunits, exhibits unique properties that it predominantly accumulates at leading edge...
Alterations in MEK1/2 occur cancers, both the treatment-naïve state and following targeted therapies, most notably BRAF MEK inhibitors BRAF-V600E-mutant melanoma colorectal cancer. Efforts were undertaken to understand effects of these mutations, based upon protein structural location, activity. Two categories alterations evaluated, those associated with either allosteric pocket or helix-A. Clinically, are rare we demonstrate that they confer resistance inhibitors, while retaining...
LONP1 is an AAA+ protease that maintains mitochondrial homeostasis by removing damaged or misfolded proteins. Elevated activity and expression of promotes cancer cell proliferation resistance to apoptosis-inducing reagents. Despite the importance in human biology disease, very few inhibitors have been described literature. Herein, we report development selective boronic acid-based using structure-based drug design as well first structures bound various inhibitors. Our efforts led several...
Changes in cellular expression of phosphoprotein enriched astrocytes 15 kDa (PEA-15) are linked to insulin resistance, tumor cell invasion, and senescence; these changes alter the activation extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein (MAP) pathway. Here, we define mechanism whereby increased PEA-15 promotes sustains ERK1/2 activation. binding prevented membrane recruitment threonine phosphorylation fibroblast receptor substrate 2alpha (FRS2alpha), a key link...
Abstract KRAS is the most frequently mutated oncogene in cancer and drives uncontrolled growth through hyperactivation of MAPK pathway. Significant progress has been made past several years to directly target KRASG12C with FDA approval sotorasib reported clinical activity adagrasib (MRTX849). Despite these remarkable breakthroughs, additional therapies that enhance depth duration response inhibitors provide opportunity build upon initial progress. SOS proteins are guanine nucleotide exchange...
<p>Supplementary Figure S6 details the improved antiproliferative activity observed with MRTX0902/osimertinib combination in EGFR mutant models, PC9 (EGFR ex19del) and NCI-H1975 L858R/T790M).</p>
<p>Supplementary Materials and Methods section includes detailed protocols for the following: Experimental Preparation of MRTX0902 Avutometinib, SOS1 Biochemical Binding Assay, SOS2 Functional Assays, KRAS-SOS1 Protein-Protiein Interaction (PPI) HTRF In-Cell Western 3D Ultra-Low Attachment (ULA) Viability Immunoblotting Densitometry Analysis, DUSP6 Quantification from Naive Tumor-Bearing Mouse Blood, Bioanalysis Pharmacokinetic Synergy CRISPR/Cas9 Screening Data Analysis Methodology,...
<p>Supplementary Figure S5 shows levels of KRAS-MAPK pathway modulation associated with coadministration MRTX0902 and adagrasib in the murine CT26 (KRAS G12C-mutant) model.</p>
<p>Supplementary Figure S2 shows the antitumor activity of MRTX0902 in LN229 (PTPN11 A72S-mutant) model, with tumor growth inhibition data displayed S2A and ERK phosphorylation graphed S2B.</p>
<div>Abstract<p><i>KRAS</i> is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of receptor tyrosine kinase (RTK)/mitogen-activated protein (MAPK) pathway. The Son Sevenless homolog 1 (SOS1) functions as a guanine nucleotide exchange factor (GEF) for RAS subfamily small GTPases represents druggable target Using structure-based drug discovery approach, MRTX0902 was identified selective potent SOS1...