A5029404868- Protein Kinase Regulation and GTPase Signaling
- Biochemical and Molecular Research
- Melanoma and MAPK Pathways
- ATP Synthase and ATPases Research
- Cytokine Signaling Pathways and Interactions
- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- Lung Cancer Research Studies
- Cancer Immunotherapy and Biomarkers
- PARP inhibition in cancer therapy
- CAR-T cell therapy research
- Radiopharmaceutical Chemistry and Applications
- Cancer Genomics and Diagnostics
- Immune cells in cancer
- Colorectal Cancer Treatments and Studies
- PI3K/AKT/mTOR signaling in cancer
- Cancer therapeutics and mechanisms
- Cancer-related Molecular Pathways
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Prostate Cancer Treatment and Research
- Computational Drug Discovery Methods
- Chronic Lymphocytic Leukemia Research
- 14-3-3 protein interactions
- Ferroptosis and cancer prognosis
Bristol-Myers Squibb (United States)
2025
Mirati Therapeutics (United States)
2019-2025
Crown College
2017
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...
KRASG12D, the most common oncogenic KRAS mutation, is a promising target for treatment of solid tumors. However, when compared to KRASG12C, selective inhibition KRASG12D presents significant challenge due requirement inhibitors bind with high enough affinity obviate need covalent interactions mutant protein. Here, we report discovery and characterization first noncovalent, potent, inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement shown be...
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...
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...
Abstract Background: KRAS inhibitors are revolutionizing the treatment of NSCLC, but clinico-genomic determinants efficacy warrant continued exploration. Methods: Patients with advanced KRASG12C-mutant NSCLC treated adagrasib (KRYSTAL-1-NCT03785249) were included in analysis. Pre-treatment NGS data collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints objective response, progression-free and overall survival. cell lines xenograft...
<p>Supplementary Methods S1. LKB1/<i>KEAP1</i> over-expression; Western Blot Analysis; KRAS-GTP Pull-Down Assay.</p>
<p>Supplementary Figure S2. <i>In vitro</i> efficacy of adagrasib in <i>KRAS</i><sup><i>G12C</i></sup>-mutant lung cancer models based on <i>STK11</i>/LKB1 and <i>KEAP1</i> status.</p>
<p>Supplementary Figure S6. Correlation of NRF2 score and survival to adagrasib monotherapy according <i>KEAP1</i> <i>STK11</i> co-mutation status.</p>
<p>Supplementary Figure S3. Adagrasib combination drug screens in KRASG12C-mutant lung cancer models.</p>
<p>Supplementary Figure S4. NRF2 score in KRASG12C-mutant NSCLC patients treated with adagrasib.</p>
<p>Supplementary Figure S8. <i>STK11</i>/LKB1 and epithelial-mesenchymal transition – EMT scores in <i>KRAS</i><sup><i>G12C</i></sup>-mutant NSCLC patients treated with adagrasib.</p>
<p>Supplementary Figure S1. Clinical outcomes to adagrasib monotherapy according <i>TP53</i>, <i>ATM</i> and <i>CDKN2A</i> co-mutation status.</p>
<p>Supplementary Figure S5. NRF2 score is associated with survival upon treatment adagrasib monotherapy.</p>
<p>Supplementary Figure S7. Clinical outcomes to adagrasib monotherapy according NRF2 score and <i>STK11</i> co-mutation status in <i>KEAP1</i><sup><i>WT</i></sup>/<i>KRAS</i><sup><i>G12C</i></sup>-mutant NSCLC patients.</p>
<div>AbstractPurpose:<p>KRAS inhibitors are revolutionizing the treatment of non–small cell lung cancer (NSCLC), but clinico-genomic determinants efficacy warrant continued exploration.</p>Experimental Design:<p>Patients with advanced <i>KRAS</i><sup><i>G12C</i></sup>-mutant NSCLC treated adagrasib [KRYSTAL-1 (NCT03785249)] were included in analysis. Pretreatment next-generation sequencing data collected per protocol. HTG EdgeSeq...
Abstract Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in cancers harboring genomic deletions of the MTAP gene, which encodes enzyme methylthioadenosine phosphorylase. Approximately one four pancreatic ductal adenocarcinoma (PDAC) cases harbor homozygous deletion gene (MTAP-del), providing promising novel targeted therapy for PDAC. The (MTA)-cooperative PRMT5 inhibitor BMS-986504 (previously known as MRTX1719) leverages elevated MTA levels present MTAP-del tumors...
The H1047R mutation of PIK3CA is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3KαH1047R over PI3KαWT crucial due to the role that plays normal cellular processes, including glucose homeostasis. Currently, only one PI3KαH1047R-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, E545K) selective PI3Kα inhibitors have also reached stage. Herein, we report design discovery a series...
Abstract First generation inhibitors of PRC2 (Polycomb Repressive Complex 2) targeting EZH2 (Enhancer Zeste Homolog achieved clinical proof-of-concept in follicular lymphoma and epithelioid sarcoma, emerging data recently revealed promising activity prostate cancer combination with AR pathway (ARPIs). Here we describe the discovery development a second inhibitor, ORIC-944, potent, selective, allosteric inhibitor that binds EED (Embryonic Ectoderm Development) subunit within complex....
Abstract MRTX1719 is an MTA-cooperative PRMT5 inhibitor that leverages the increased concentration of metabolite MTA in cancer cells harboring a homozygous deletion MTAP gene (MTAP del) under investigation clincial trials. preferentially binds to PRMT5•MTA complex selectively inhibit PRMT5, essential for all cells, del while sparing activity normal MTAP-wildtype cells. occurs ~10% cancers, and these patients exhibit remarkably poor survival. Among pancreatic cancer, ~ 25% ~30% have...
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....