A5009792252- Protein Kinase Regulation and GTPase Signaling
- Melanoma and MAPK Pathways
- HER2/EGFR in Cancer Research
- Cancer Immunotherapy and Biomarkers
- Radiopharmaceutical Chemistry and Applications
- CAR-T cell therapy research
- Immune cells in cancer
- Ferroptosis and cancer prognosis
- Biochemical and Molecular Research
- S100 Proteins and Annexins
- Glioma Diagnosis and Treatment
- Computational Drug Discovery Methods
- Click Chemistry and Applications
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Advanced Biosensing Techniques and Applications
- Cellular Mechanics and Interactions
- Chemical Synthesis and Analysis
- Advanced Breast Cancer Therapies
- Viral Infectious Diseases and Gene Expression in Insects
- Peptidase Inhibition and Analysis
- Drug Transport and Resistance Mechanisms
- Immunotherapy and Immune Responses
- Microbial Natural Products and Biosynthesis
- PI3K/AKT/mTOR signaling in cancer
Mirati Therapeutics (United States)
2019-2024
Scripps Research Institute
2024
Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, inhibits KRAS-dependent signaling. demonstrated pronounced tumor regression 17 26 (65%) KRASG12C-positive cell line- patient-derived xenograft models from multiple types, objective responses observed patients with lung colon...
Abstract KRASG12C inhibitors, including MRTX849, are promising treatment options for KRAS-mutant non–small cell lung cancer (NSCLC). PD-1 inhibitors approved in NSCLC; however, strategies to enhance checkpoint inhibitor therapy (CIT) needed. mutations smoking-associated transversion associated with high tumor mutation burden, PD-L1 positivity, and an immunosuppressive microenvironment. To evaluate the potential of MRTX849 augment CIT, its impact on immune signaling response CIT was...
Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing a privileged rewiring cellular biochemistry. While rational design strategies can expedite the discovery heterobifunctional CIPs, molecular glues have predominantly been discovered by serendipity. Envisioning prospective approach to discover for pre-selected target, we hypothesized that pre-existing ligands could be systematically decorated with chemical modifications protein-ligand surfaces are tuned...
Abstract After decades of research, covalent inhibitors targeting KRASG12C are entering clinical trials. mutations found in 14% non-small cell lung cancer (NSCLC) adenocarcinoma as well several other types at lower frequencies. smoking-associated transversion that associated with a relatively high total mutation burden (TMB) and PD-L1 positivity. Although pembrolizumab is clinically active KRAS-mutant NSCLC, response rates remain modest strategies to augment the activity checkpoint inhibitor...
Abstract The ability to effectively target mutated KRAS has remained elusive despite decades of research. By solving a series co-crystal structures coupled with iterative structure-based drug design, substituted tetrahydropyridopyrimidines were identified as selective, covalent inhibitors mutant G12C. MRTX1257 emerged research tool compound that demonstrates the irreversibly modify G12C, trap it in its inactive GDP-bound state, and inhibit ERK1/2 an IC50 value 1 nM. Therefore, studies...
Abstract The ability to effectively target mutated KRAS has remained elusive despite decades of research. MRTX849 was identified via structure-based drug design as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties. is presently under evaluation in clinical trials its discovery disclosed here for the first time. demonstrated selective modification mutant cysteine residue at amino acid 12 GDP-bound inhibited KRAS-dependent signaling vitro vivo....
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...
The ability to effectively target mutated KRAS has remained elusive despite decades of research. By solving a series co-crystal structures coupled with iterative structure-based drug design, substituted tetrahydropyridopyrimidines were identified as selective, covalent inhibitors mutant G12C. MRTX1257 emerged research tool compound that demonstrates the irreversibly modify G12C, trap it in its inactive GDP-bound state, and inhibit ERK1/2 an IC50 value 1 nM. Therefore, studies designed...
Abstract KRAS G12C is a driver mutation and the most frequent in lung cancer. The ability to effectively target mutated has remained elusive despite decades of research. A structure-based drug design discovery program identified mutant-selective, covalent inhibitors with low nanomolar cell potency favorable oral properties. MRTX1257 research tool compound that demonstrates selective irreversible modification inhibits ERK1/2 phosphorylation an IC50 value 1 nM H358 cell-based assay. was...
Abstract The ability to effectively target mutated KRAS has remained elusive despite decades of research. recent identification KRASG12C inhibitors provided an effective treatment option for patients harboring this particular mutation and also insight toward targeting other mutants, including KRASG12D. MRTX1133 was identified via a structure-based drug design (SBDD) strategy as potent, selective, non-covalent KRASG12D inhibitor directed at the switch II binding pocket. demonstrated...
<div>Abstract<p>KRAS<sup>G12C</sup> inhibitors, including MRTX849, are promising treatment options for KRAS-mutant non–small cell lung cancer (NSCLC). PD-1 inhibitors approved in NSCLC; however, strategies to enhance checkpoint inhibitor therapy (CIT) needed. <i>KRAS<sup>G12C</sup></i> mutations smoking-associated transversion associated with high tumor mutation burden, PD-L1 positivity, and an immunosuppressive microenvironment. To evaluate...
<p>Supplementary Material</p>
<p>Figures S1-S7</p>
<p>Figures S1-S7</p>
<p>Supplementary Material</p>
<div>Abstract<p>KRAS<sup>G12C</sup> inhibitors, including MRTX849, are promising treatment options for KRAS-mutant non–small cell lung cancer (NSCLC). PD-1 inhibitors approved in NSCLC; however, strategies to enhance checkpoint inhibitor therapy (CIT) needed. <i>KRAS<sup>G12C</sup></i> mutations smoking-associated transversion associated with high tumor mutation burden, PD-L1 positivity, and an immunosuppressive microenvironment. To evaluate...
<div>Abstract<p>Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRAS<sup>G12C</sup> inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRAS<sup>G12C</sup>, inhibits KRAS-dependent signaling. demonstrated pronounced tumor regression 17 26 (65%) KRAS<sup>G12C</sup>-positive cell line–...
<p>Supplementary Composite Figure File</p>
<p>Supplementary Table S7</p>
<p>Supplementary methods and Tables</p>
<p>Supplementary Table S8</p>
<p>Supplementary Composite Figure File</p>
<p>Supplementary Table S8</p>