Shilpi Khare
A5060530589- ATP Synthase and ATPases Research
- Biochemical and Molecular Research
- Cytokine Signaling Pathways and Interactions
- Protein Tyrosine Phosphatases
- Protein Kinase Regulation and GTPase Signaling
- Cancer-related Molecular Pathways
- PI3K/AKT/mTOR signaling in cancer
- Microtubule and mitosis dynamics
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Cancer Treatment and Pharmacology
- Advanced Breast Cancer Therapies
- Lung Cancer Treatments and Mutations
- Ubiquitin and proteasome pathways
- Colorectal Cancer Treatments and Studies
- Cell death mechanisms and regulation
Mirati Therapeutics (United States)
2022-2024
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...
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...
SOS1 and SOS2 are guanine nucleotide exchange factors that mediate RTK-stimulated RAS activation. Selective SOS1:KRAS PPI inhibitors currently under clinical investigation, whereas there no reports to date of SOS2:KRAS inhibitors. activity is implicated in MAPK rebound when divergent mutant cell lines treated with the inhibitor BI-3406; therefore, therapeutic interest. In this report, we detail a fragment-based screening strategy identify X-ray cocrystal structures five diverse fragment hits...
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...
Abstract Genetic alterations in the RAS-MAPK pathway are one of most frequent causes human cancers. While targeted therapies approved for patients harboring mutations KRAS G12C advanced or metastatic non-small cell lung cancer, there remains a need an effective therapy cancers characterized by additional across cancer types. Previous studies have shown that genetic pharmacological inhibition Son Sevenless homolog 1 (SOS1) demonstrates antiproliferative activity cells addicted to signaling,...
<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...
<p>Supplementary Figure S7 shows the improved antiproliferative activity observed with MRTX0902/avutometinib combination in KRAS-MAPK pathway mutant models, LN229 (PTPN11 A72S) and NCI-H1435 (NF1 K615N).</p>
<p>Supplementary Figure S1 details the genetic vulnerabilities and modifiers of response associated with combination treatment MRTX0902 adagrasib in KRAS G12C-mutant MIA PaCa-2 (S1A, S1B, S1D, S1E) LU99 (S1C) cell lines <i>in vitro</i> vivo</i>.</p>
<p>Supplementary Figure S3 details the antitumor effects and gene set enrichment analysis data associated with coadministration of MRTX0902 adagrasib in KRAS G12C-mutant human tumor xenograft models.</p>
<p>Supplementary Figure S8 details the antitumor effects associated with coadministration of MRTX0902 and adagrasib in MIA PaCa-2 (KRAS G12C-mutant) model.</p>
<p>Supplementary Figure S4 shows levels of KRAS-MAPK pathway modulation associated with coadministration MRTX0902 and adagrasib in the MIA PaCa-2 (KRAS G12C-mutant) model.</p>
Abstract Osimertinib is a third generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor recommended as first line therapy in patients with advanced non-small lung cancer (NSCLC) characterized by EGFR activating mutations (exon 19 deletions and exon 21 L858R) the resistance associated 20 T790M mutation, which present approximately 40-55% of following treatment generation EGFR-targeting inhibitors. Unfortunately, osimertinib monotherapy inevitably leads to...
Abstract KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of MAPK pathway. Recent data has consistently demonstrated co-dependencies mutant-KRAS with extrinsic proteins that augment GTP-loading. Son Sevenless homolog 1 (SOS1) proximal these to functions as a guanine nucleotide exchange factor (GEF) for RAS subfamily small GTPases, thus representing highly sought-after druggable target. Utilizing structure-based drug...
Abstract KRAS mutations are the most common activating in human cancer that ultimately lead to hyperactivation of MAPK pathway and uncontrolled growth. functions as a small GTPase cycles through its GTP-loaded “on” state GDP-loaded “off” state, highly regulated process is crucial for normal cell proliferation survival. The guanine nucleotide exchange factor (GEF) SOS1 plays critical role this by regulating “on/off” KRAS. protein-protein interaction between facilitates turnover from inactive...