MRTX1133 / BMS - LARVOL DELTA

Discovery of KRAS-G12D degraders via exploration of various E3 ligases. (PubMed, Eur J Med Chem) - "In this study, we designed, synthesized and evaluated a series of KRAS-G12D degraders that recruit one of four E3 ligases (CRBN, VHL, DCAF1, or KLHDC2) using a common KRAS-G12D binder derived from the KRAS-G12D inhibitor MRTX1133...In contrast, KLHDC2- and DCAF1-based degraders failed to induce KRAS-G12D degradation, potentially due to suboptimal ternary complex formation or insufficient E3 ligase compatibility. These findings highlight the importance of E3 ligase selection in the development of effective KRAS-G12D degraders."

Journal • Targeted Protein Degradation • CRBN • KRAS

Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations (Nature) - "We found that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency. Anabolic pathways, autophagy and glycolysis were also profoundly altered. However, most strikingly, mitochondrial remodeling was evident, persisting into a therapy-resistant state. The resulting vulnerability to the induction of ferroptotic cell death via the combination of vertical SHP2/MEK1/2 with glutathione peroxidase (GPX4) inhibition was largely independent of the PDAC molecular subtype and was confirmed with direct targeting of RAS."

Preclinical • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Computational repurposing of approved drugs targeting KRAS G12D and EGFR for colorectal cancer therapy. (PubMed, PLoS One) - "This in silico study predicts Carteolol as a potential dual-targeting therapeutic agent, requiring biochemical and cellular validation before clinical relevance can be established."

Journal • Colorectal Cancer • Oncology • Solid Tumor • EGFR • KRAS

Exploring the GDP binding to KRas WT, G12C, G12D, G12R, and G12V and bound with MRTX1133 using steered molecular dynamics. (PubMed, Eur Biophys J) - No abstract available

Journal • KRAS

AMPK drives metabolic adaptation and resistance to KRAS inhibition in pancreatic cancer (LCC 2026) - "To test this, we investigated the effects of the selective AMPK inhibitor BAY-3827 in combination with the KRAS-G12D inhibitor MRTX1133. AMPK loss enhanced the efficacy of MRTX1133 both in vitro and in vivo. Together, these data identify AMPK activation as an adaptive resistance mechanism to KRAS inhibition and highlight AMPK as a potential therapeutic target to improve the durability of oncogene-specific therapies."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • AMPK • KRAS • SLC3A2 • TP53

Co-targeting thrombospondin-1 (THBS-1) to improve KRAS inhibitor and chemotherapeutic efficacy in pancreatic cancer (LCC 2026) - "Mirati's G12D KRAS inhibitor, MRTX1133, can cause a >50% decrease in mouse PC tumour burden2. Pan-KRAS inhibitors act on all KRAS mutations, including RMC-6236 (Revolution Medicines) and BI-2493 (Boehringer Ingelheim)3,4... Future work will include trialling our novel combination therapy via subcutaneous and orthotopic (intra-pancreatic) in vivo models. Overall, we aim to assess THBS-1 as a potential co-target to improve the efficacy and durability of these promising KRAS inhibitors and standard-of-care chemotherapy. Siegel, R. L., Giaquinto, A. N. & Jemal, A. Cancer statistics, 2024."

Clinical • Fibrosis • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • CD22 • KRAS • NID2 • SMAD4 • TGFB1

Ferritin-based nanocarrier delivery of KRAS G12D inhibitor in pancreatic adenocarcinoma cells and patient-derived organoids: A novel approach for treatment. (PubMed, Protein Sci) - "While KRAS was historically considered undruggable, mutant-specific inhibitors, including non-covalent KRAS G12D inhibitor MRTX1133, have emerged...Efficacy in patient-derived organoids was comparable. This study demonstrates the potential of this nanomedicine platform for targeted delivery of KRAS mutant-specific inhibitors to human tumors."

Journal • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

The combination of BCL-xL PROTAC and mTOR inhibitor sensitizes pancreatic ductal adenocarcinoma to KRAS G12D inhibitor treatment by enhancing apoptosis induction. (PubMed, bioRxiv) - "KRAS inhibitors, including KRAS G12D inhibitor MRTX1133, are promising therapeutics against KRAS-mutated pancreatic ductal adenocarcinoma (PDAC), but drug resistance limits their efficacy. Our study reveals that robust induction of apoptosis using a combination of BCL-xL PROTAC degrader and an mTOR inhibitor, significantly enhances MRTX1133 efficacy in PDAC models without increasing toxicity to normal tissues."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Targeted Protein Degradation • BCL2L1 • KRAS • PMAIP1

Resistance to the KRASG12D Inhibitor MRTX1133 is Associated with Increased Sensitivity to BET Inhibition. (PubMed, Mol Cancer Ther) - "In murine models of MRTX1133-resistant PDAC, BET inhibition cooperated with MRTX1133 to markedly extend overall survival. As BET inhibitors are currently under clinical testing, the combination of MRTX1133 and BET inhibitors warrants further investigation, particularly in tumors that have developed resistance to KRAS inhibition."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • EP300 • FOSL1 • KRAS

Effect of ROCK2 signaling on resistance to KRAS inhibitors in pancreatic cancer. (ASCO-GI 2026) - " Pancreatic cells resistant to KRAS G12D inhibitor MRTX1133 or the pan-RAS inhibitor RMC-6236 were generated by exposing the cells to increasing concentrations of the drug. Our findings suggest that increased ROCK2 signaling mediates resistance to KRAS inhibitors in pancreatic cancer and targeting ROCK2 represents a promising approach to overcome resistance to KRAS inhibitors."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • KRAS

Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors. (PubMed, Nat Commun) - "RAS inhibitors MRTX1133 and RMC-6236 alter Switch-I/II conformations, thereby blocking SKP assembly more effectively than they disrupt preformed complexes. This MRAS mutant can form an SMP complex, but MRTX1133 blocks its assembly, demonstrating the feasibility of dual SKP and SMP targeting. Overall, our findings define isoform-specific differences in SHOC2-RAS-PP1C complex formation and support a strategy to prevent both SKP and SMP assemblies to overcome resistance in RAS-driven cancers."

Journal • Genetic Disorders • Oncology • HRAS • KRAS • NRAS

KRASAVA-An Expert System for Virtual Screening of KRAS G12D Inhibitors. (PubMed, Int J Mol Sci) - "For the reference inhibitor MRTX1133, we reproduced the crystal structure pose with an RMSD of 0.76 Å (PDB ID: 7T47). The key interactions with amino acid residues Asp12, Asp69, His95, Arg68, and Gly60, identified for both MRTX1133 and our proposed compounds, demonstrate a strong consistency between the molecular docking and QSAR results."

Journal • Pain • KRAS

KRAS mutation-driven O-GlcNAcylation of CLDN18.2 enhances the progression of pancreatic cancer and reduces the efficacy of CLDN18.2-targeted therapy. (PubMed, Gut) - "KRAS mutations and hyperglycaemia drive O-GlcNAcylation of CLDN18.2 at its C-terminal T204 site. O-GlcNAcylated CLDN18.2 promotes poor prognosis and reduces the effectiveness of CLDN18.2-targeted therapies. Low dose MRTX1133 restores CLDN18.2 membrane localisation by reducing its O-GlcNAcylation and augments CLDN18.2-targeted therapy efficacy, offering a novel combinatorial strategy for KRAS-mutant PDAC."

Journal • Diabetes • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CLDN18 • KRAS • PDX1 • PTPN1

PDK1 and YAP1/TEAD signaling drive acquired KRAS inhibitor resistance in KRAS-mutant non-small cell lung cancer. (PubMed, bioRxiv) - "While historically considered undruggable, recent breakthroughs have seen the FDA approval of two potent KRAS G12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849)...To elucidate mechanisms of acquired resistance, we generated a panel of resistant cell lines to the allele-specific KRAS inhibitors MRTX849 and MRTX1133 and observed an increased activation of the PDK1 and YAP1/TEAD signaling pathways...Furthermore, overexpression studies revealed that forced expression of either PDK1 or YAP1 led to increased resistance to KRAS inhibition in the sensitive lines. Taken together, our findings suggest that co-targeting PDK1 or YAP1/TEAD might be a potential approach to overcoming resistance to KRAS inhibition in NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PDK1 • YAP1

In-Source Fragmentation of Pyrrolidine-Containing KRAS Scaffolds Leads to Enhanced Structure Elucidation and Tandem Mass Spectral Quality. (PubMed, J Am Soc Mass Spectrom) - "We demonstrate the successful application of this optimized workflow to characterize GDC-6036, its synthetic intermediate, and structurally distinct KRAS inhibitors (Adagrasib and MRTX1133) across a chromatographic time scale. This approach offers a universal tool for enhancing the structure elucidation of challenging basic compounds, critical for supporting pharmaceutical process development."

Journal • KRAS

An overview of KRAS-targeting therapies for colorectal cancer in phase I and II development. (PubMed, Expert Opin Investig Drugs) - "Allele-specific inhibitors are likely to find their place in combinations that suppress adaptive bypass (e.g. SOS1/SHP2, MEK/ERK, EGFR) while leveraging immunotherapy or metabolic vulnerabilities. Prospective biomarker integration and resistance-informed trial designs will be decisive in translating early signals into durable patient benefit."

IO biomarker • Journal • P1 data • Review • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • EGFR • KRAS • MSI

Antimetastatic effects of MRTX1133 KRAS G12D specific inhibitor in a liver metastatic model of pancreatic ductal adenocarcinoma. (PubMed, Sci Rep) - "MRTX1133 induced alterations associated with mesenchymal-to-epithelial transition; furthermore, lower levels of activated Erk, altered FAK expression, and activation were observed. In addition to the antiproliferative effects of MRTX1133, our in vitro and in vivo results indicate the importance of MRTX1133 as a potential antimetastatic drug in PDAC therapy."

Journal • Hepatocellular Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • PTK2

Dual Inhibition of KRAS G12D and PI3K/BRD4 Signaling Overcomes Therapeutic Resistance in Pancreatic Cancer. (PubMed, Acta Biomater) - "When combined with the KRAS G12D inhibitor MRTX1133, MDP5 resensitized resistant cancer cells. This combination synergistically enhanced apoptosis and proliferation inhibition, outperforming the standard-of-care, Gemcitabine (GEM)...Mechanistically, dual inhibition suppresses AKT/YAP signaling, depletes CD44+/ALDH+ cells, and shifts the tumor immune milieu (↑CD8a, ↑CD86, ↓Ly-6G). By integrating molecular targeting with multi-pathway blockade, this work addresses two major barriers-resistance and delivery-and outlines a generalizable strategy to improve precision nano therapy for KRAS-mutant pancreatic cancer."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRD4 • CD8 • CD86 • KRAS • MUC4 • YAP1

Simultaneous targeting of KRAS and CDK4 synergistically induces durable growth arrest in pancreatic cancer cells. (PubMed, Cell Death Dis) - "We show that the KRAS-G12C inhibitor Sotorasib synergizes with the CDK4/6 inhibitor Palbociclib to eliminate pancreatic ductal adenocarcinoma (PDAC) cells and organoids harboring KRAS-G12C mutations...Additionally, the KRAS-G12D inhibitor MRTX1133 cooperated with Palbociclib to suppress growth of KRAS-G12D-mutant PDAC cells...Single-cell RNA sequencing suggested that Palbociclib treatment induces tumor vascularization, perhaps contributing to the lack of drug synergy observed in vivo. In summary, our findings demonstrate the therapeutic potential of enhancing cell cycle restriction point activation in KRAS inhibitor-based therapies, while emphasizing the importance of placing combination therapies into a suitable context."

Journal • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDK4 • CDKN1B • E2F1 • KRAS

Discovery of Pyrazoloquinazoline Analogues as Orally Bioavailable KRAS-G12D Inhibitors. (PubMed, J Med Chem) - "Compound 53a exhibited comparable binding to KRAS-G12D (ΔTm = 12.1 °C) and potent in vitro activities (IC50 values of 8.4 nM and 19.5 nM against p-ERK and proliferation of AsPC-1 cells, respectively), compared to those of MRTX1133 as a reference standard...In vivo study showed that 53a significantly inhibited tumor growth in the AsPC-1 xenograft mouse model by inhibiting KRAS-G12D. These findings support 53a as a promising lead candidate for the development of selective KRAS-G12D targeted cancer therapies."

Journal • Oncology • KRAS

PCNA Inhibition Enhances the Antitumor Activity of KRAS-Targeted Therapies in Pancreatic Cancer. (PubMed, bioRxiv) - "Robust antitumor activity of AOH1996 in combination with RMC-6236 was observed in PDAC tumoroids. In vivo , the combination of AOH1996 with sotorasib or MRTX1133 reduced tumor growth rates compared to single-agent therapy, with no impact on mouse body weight. Residual tumor analysis showed sustained pERK and Myc inhibition in the combination arm. In conclusion, combination of AOH1996 with KRAS inhibitors is a promising therapeutic strategy for KRAS-driven PDAC, warranting further clinical investigation."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • PCNA

Targeting KRAS G12D: Advances in Inhibitor Design. (PubMed, Thorac Cancer) - "Significant progress has been made in the development of small-molecule inhibitors: non-covalent inhibitors (e.g., MRTX1133) exploit ionic interactions (salt bridges) with the mutant aspartic acid residue to achieve high affinity and selectivity; novel covalent strategies are emerging, including strain-release alkylation and tri-complex inhibitors (e.g., RMC-9805). The article further evaluates the status of candidate drugs currently in clinical trials and addresses the critical challenges of acquired resistance, which may arise through secondary mutations or bypass signaling pathways. Finally, it emphasizes future directions, including the optimization of drug delivery via nanoparticles and the implementation of combination therapies to enhance efficacy and achieve durable clinical responses."

Journal • Review • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • KRAS

Targeted and immunotherapy strategies in pancreatic ductal adenocarcinoma: Recent developments and insights. (PubMed, Hepatobiliary Pancreat Dis Int) - "Several investigational and approved agents, including KRAS inhibitors (MRTX1133, sotorasib), PARP inhibitors (olaparib), and immune checkpoint inhibitors (pembrolizumab), have demonstrated encouraging results, particularly in combination regimens. These findings provide valuable insights into future research and clinical strategies aiming at improving the prognosis of PDAC."

Journal • Review • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Co-targeting KRAS and Exportin1 as an effective therapeutic strategy for KRASG12D mutant pancreatic ductal adenocarcinoma. (PubMed, bioRxiv) - "Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models. By enhancing KRASG12D inhibitor activity and potentially reducing the required therapeutic dose, this combination approach offers a novel means to delay or overcome resistance. These findings provide a strong preclinical rationale for clinical trials evaluating KRAS inhibitors in combination with XPO1 inhibitors and may significantly improve outcomes for a substantial subset of PDAC patients who currently lack effective targeted treatment options."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CCND1 • DUSP6 • EIF4EBP1 • KRAS • XPO1

Actionable mutations in pancreatic cancer: where targeted therapies are making a difference. (PubMed, BMJ Open Gastroenterol) - "It demonstrates that targeting these lesions can yield outcomes that meet or exceed the benchmarks set by the NAPOLI-1 trial (liposomal irinotecan plus 5-fluorouracil and leucovorin), with a median overall survival of 6.2 months and progression-free survival of 3.1 months. Objective response rates reach 33% with adagrasib in KRAS G12C PDAC, 22% with olaparib maintenance in germline BRCA1/2 cancers, and over 50% with RET or NTRK inhibitors with fusion alterations; pembrolizumab produces durable benefit in the 1-3% of tumours that are MSI-H/dMMR. Emerging data highlight NRG1 fusions (overall response rate 42% with zenocutuzumab), HER2 amplification, MTAP deletion with PRMT5 dependency and variant-specific (MRTX1133) or pan-RAS (daraxonrasib) inhibitors as the next frontier...Taken together, these advances represent a substantive therapeutic progress in PDAC over the past decades, even though they currently apply to a minority of patients. These findings underscore the..."

Journal • Review • Gene Therapies • Microsatellite Instability • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRCA1 • BRCA2 • HER-2 • KRAS • MSI • MTAP • NRG1 • NTRK