Allan Hebbert
A5011797617- Cancer-related gene regulation
- ATP Synthase and ATPases Research
- Biochemical and Molecular Research
- Cytokine Signaling Pathways and Interactions
- Protein Tyrosine Phosphatases
- Synthesis and Catalytic Reactions
- PARP inhibition in cancer therapy
- Cell death mechanisms and regulation
- 14-3-3 protein interactions
- HER2/EGFR in Cancer Research
- Epigenetics and DNA Methylation
- Protein Kinase Regulation and GTPase Signaling
- Cancer-related Molecular Pathways
- PI3K/AKT/mTOR signaling in cancer
- Ubiquitin and proteasome pathways
- Lung Cancer Treatments and Mutations
- Cancer, Lipids, and Metabolism
- Cancer, Hypoxia, and Metabolism
- Colorectal Cancer Treatments and Studies
Mirati Therapeutics (United States)
2021-2024
RIKEN BioResource Research Center
2023
Abstract Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of small-molecule inhibitors that recapitulate phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in presence MTA, which is elevated MTAP del cancers, and PRMT5-dependent activity cell viability with >70-fold selectivity HCT116 compared wild-type (WT) cells. demonstrated...
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 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 Previous studies have shown that cancer cell lines with homozygous deletion of the MTAP gene (MTAP del), are selectively sensitive to shRNA-mediated PRMT5 inhibition or MTA-cooperative inhibitors. is a methyltransferase adds symmetric dimethyl arginine marks various proteins essential for viability whereas responsible metabolizing MTA as part methionine salvage pathway. In del cells, accumulates and partially inhibits activity by directly competing SAM, universal methyl donor...
Abstract Previous studies identified PRMT5 as a synthetic lethal target for cancers harboring homozygous deletion of the MTAP gene (MTAP del) whereby accumulation MTA, substrate, partially inhibits activity leading to an increased dependency on PRMT5. MRTX1719 is MTA cooperative inhibitor that preferentially binds PRMT5/MTA complex, leveraging concentration associated with selectively del cancer cells while sparing normal tissues resulting in broad therapeutic index. adjacent and co-deleted...
Abstract Introduction: Clinically active KRASG12C inhibitors have represented a key research breakthrough and led to novel treatment options for lung, colorectal other cancer patients harboring this mutation. While with are clinically in the majority of patients, depth duration response is variable most ultimately progress. This variation therapeutic highlights need better understanding drug mechanism action identification rational combination strategies. Oncogenic KRAS mutations...
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,...
Abstract Introduction: KRASG12D is the most common KRAS mutation and present in approximately 34% of pancreatic cancer, 10-12% colorectal 4% lung adenocarcinoma a number other cancer types. We previously identified MRTX1133, potent, selective, non-covalent inhibitor. The advancement MRTX1133 to clinical trials warrants continued study role pathogenesis progression. Methods: Previous pharmacodynamic pharmacogenomic profiling sensitive partially resistant models mechanisms implicated limiting...
<p>SDMA and MTAP IHC TMA data</p>
<p>Supplemental in vivo pharmacodynamic characterization of MRTX1719</p>
<p>Supplemental in vitro and vivo efficacy of MRTX1719</p>
<p>Supplemental pharmacodynamic effects of MRTX1719 in patients</p>
<p>Materials and methods related to supplemental data</p>
<p>Supplemental in vitro and vivo efficacy of MRTX1719</p>
<p>Materials and methods related to supplemental data</p>
<p>Supplemental biochemical and cellular characterization of MRTX1719</p>
<p>Supplemental pharmacodynamic effects of MRTX1719 in patients</p>
<p>Co-culture experiments with MTAP-expressing fibroblasts</p>
<p>SDMA and MTAP IHC TMA data</p>
<p>Supplemental biochemical and cellular characterization of MRTX1719</p>
<p>Co-culture experiments with MTAP-expressing fibroblasts</p>
<p>Supplemental in vivo pharmacodynamic characterization of MRTX1719</p>
<p>Thermal shift PRMT5 inhibitor data</p>