MRTX1133 / BMS - LARVOL DELTA

RNA processing kinase inhibitors and epigenetic inhibitors in combination with oncology drugs or investigational agents in multi-cell type patient-derived tumor cell line spheroids. (PubMed, Res Sq) - "We investigated the activity of two CLK inhibitors, cirtuvivint and CC-671, and the LSD1 inhibitor iadademstat alone and in combination with anticancer drugs or investigational agents...These agents included the XPO1 inhibitor, eltanexor, and the KRAS G12D specific inhibitor MRTX-1133 which had activity in tumor lines harboring the KRAS G12D mutation. LSD1 inhibition was effective with ubiquitin proteasome pathway inhibitors. The full data sets are available on PubChem."

IO biomarker • Journal • Preclinical • Oncology • Targeted Protein Degradation • KRAS

Potent antitumor activity of the KRASG12D inhibitor MRTX1133 in pancreatic cancer: Augmenting the nanoparticle-paclitaxel chemotherapy response. (ASCO 2025) - "The combination of nab-paclitaxel and gemcitabine (NPT-GEM) is the current standard treatment for advanced and metastatic PDAC, providing a median survival of approximately 8.5 months. The significant antitumor efficacy of MRTX1133, especially when combined with the nanoparticle-paclitaxel chemotherapy regimen, holds substantial promise for enhancing the clinical management of patients with KRASG12D-mutant PDAC."

Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CASP3 • CDKN2A • KRAS • MIA • SMAD4 • TP53

Resistance to the KRAS G12D Inhibitor MRTX1133 is Associated with Increased Sensitivity to BET Inhibition. (PubMed, bioRxiv) - "Here, we demonstrate that BET inhibition is effective in PDAC with acquired resistance to KRAS inhibitors. As BET inhibitors are under clinical testing, the combination of KRAS and BET inhibitors warrants consideration in PDAC patients."

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

IBI3019, a first-in-class EGFR/CDH17/CD16A tri-specific antibody, demonstrated potent efficacy against CRC and an excellent safety profile in preclinical studies (AACR 2025) - "Inhibition of EGFR signaling is clinically effective in colorectal cancer (CRC) as evidenced by the approval for Cetuximab in combination with chemotherapy or Encorafenib, a BRAF inhibitor, and the promising clinical results when combined with KRAS inhibitors, such as Adagrasib or Sotorasib...Additionally, IBI3019 incorporates a high affinity CD16A single domain antibody that mediates stronger antibody-dependent cell cytotoxicity (ADCC) than IgG1 used in Cetuximab or the low fucosylated Fc of Amivantamab, a bispecific antibody targeting c-MET and EGFR, both in vitro and in vivo...It exhibited strong synergy with Fulzerasib, a KRAS G12C inhibitor and MRTX1133, a KRAS-G12D inhibitor...IBI3019 is a highly optimized FIC molecule with enhanced EGFR blocking capability and ADCC, maximizing tumor inhibition while minimizing toxicity. Its superior efficacy and safety profile support further clinical evaluation."

Preclinical • Trispecific • Colorectal Cancer • Oncology • Solid Tumor • CDH17 • FCGR3A • KRAS • MET

Targeting DNA helicase CMG complex and NFκB2-driven drug-resistant transcriptional axis to effectively treat KRASG12D-mutated pancreatic cancer. (PubMed, Exp Hematol Oncol) - "To overcome NFκB2-driven resistance mechanisms, we explored a triple-targeting strategy that addresses metabolic and genomic plasticity in addition to actively intercepting cell division. This approach combines MRTX1133, Bedaquiline, and the NFκB2 inhibitor SN52, offering a novel therapeutic avenue to treat aggressive pancreatic cancer and potentially improve patient outcomes."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDC45 • GINS2 • KRAS

Combination therapy of avutometinib and MRTX1133 synergistically suppresses cell growth by inducing apoptosis in KRASG12D-mutated pancreatic cancer. (PubMed, Mol Cancer Ther) - "In in vivo experiments, the combination therapy markedly delayed tumor growth compared to either therapy alone. Therefore, the combination of avutometinib and MRTX1133 may represent a promising therapeutic approach for KRASG12D-mutated pancreatic cancer."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BIRC5 • KRAS

Acetylation-induced degradation of ECHS1 enhances BCAA accumulation and proliferation in KRAS-mutant colorectal cancer. (PubMed, J Exp Clin Cancer Res) - "Limiting BCAA intake not only suppresses tumor growth in KRAS-mutant CRC but also enhances the efficacy of the KRAS G12D inhibitor MRTX1133 and the monoclonal antibody bevacizumab. Our findings reveal a previously unknown regulatory mechanism of ECHS1 in CRC and offer new potential therapeutic targets."

Journal • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • KRAS

Design, Synthesis, Anticancer Evaluation and Molecular Docking of Pyrimidine, Pyrido[4,3-d]pyrimidine and 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidine Derivatives as Novel KRAS-G12D Inhibitors and PROTACs. (PubMed, Pharmaceuticals (Basel)) - "While allosteric inhibitors targeting the SWII pocket (e.g., MRTX1133) show promise, limited chemical diversity and paradoxical cellular/enzymatic activity relationships necessitate the exploration of novel scaffolds...Two PROTACs were designed but showed no clear advantage over 10k. This study provides valuable insights for KRAS-targeted drug development."

Journal • Biliary Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation • KRAS

Combinatorial screen with standard of care and selected anticancer agents identifies multiple combinations with activity against a panel of patient-derived colorectal organoids (AACR 2025) - "Following compound addition, organoid growth was measured by live bright field imaging every 24 h and cell viability was determined by CellTiter-Glo 3D at 48 h and 168 h. Modest responses were observed in most models from the combination of leucovorin with 5-FU; however, >1 log of cytotoxicity was observed in only several models. The panel was more responsive to FOLFOX, which was consistent with the sensitivity of models to oxaliplatin. Responses to TAS-102 varied and >1 log of cytotoxicity was observed in several models...Combination of the BCL-2/BCL-xL inhibitor pelcitoclax plus cobimetinib achieved >1 log of cytotoxicity in most organoid models. Combinations of cobimetinib with the EGFR inhibitors erlotinib, afatinib or cetuximab demonstrated synergy in many organoids according to the Bliss independence model and frequently achieved ≥1 log of cytotoxicity...The combination of cobimetinib and MRTX1133 had synergistic activity by Bliss independence in multiple..."

Clinical • Oncology • BCL2 • BCL2L1 • BRAF • KRAS • PIK3CA

KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma. (PubMed, Transl Oncol) - "This dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN1A • KRAS

GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy as single agent and in combination with other anticancer therapies in preclinical models (AACR 2025) - P1/2 | "Furthermore, GFH375 was more potent than other KRAS G12D inhibitors (e.g. RMC-9805, MRTX1133) in reducing the level of RAF1-bound active KRAS G12D-GTP (ON) and inhibiting cell proliferation in MEFs expressing human KRAS G12D...Combination with the RAF/MEK clamp avutometinib also enhanced the anti-tumor efficacy of GFH375...Altogether, GFH375 is a potent and selective orally active inhibitor of KRAS G12D (ON/OFF) and demonstrated promising anti-tumor activity in multiple KRAS G12D tumor models in vivo as single agent and in combination with other anticancer therapies including cetuximab. These results support the ongoing clinical evaluation of GFH375 for treatment of patients with KRAS G12D mutant cancers (NCT06500676)."

Combination therapy • Preclinical • Colorectal Cancer • Endometrial Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

A novel PCNA inhibitor AOH1996 demonstrates pre-clinical efficacy in pancreatic ductal adenocarcinoma models (AACR 2025) - "We found that KRAS G12D inhibitor (MRTX1133) in combination with AOH1996 enhanced cytotoxicity in several PDAC cell lines at lower MRTX1133 concentrations, potentially reducing toxic side effects. We also observed enhanced efficacy of the chemotherapeutic agent oxaliplatin, which is a platinum compound in the FOLFIRINOX regimen, in combination with AOH1996. Collectively, our results show that AOH1996 is a promising agent for PDAC treatment which potentiates chemotherapy, and targeted KRAS G12D inhibitors. In vivo xenograft studies combining AOH1996 and KRAS inhibitors are ongoing."

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

The KRASG12Dinhibitor MRTX1133 demonstrates significant antitumor activity and enhances nanoparticle-paclitaxel chemotherapy outcomes in pancreatic cancer (AACR 2025) - "The combination of nab-paclitaxel and gemcitabine (NPT-GEM) represents the standard treatment for advanced and metastatic PDAC, yielding a median survival of approximately 8.5 months. These findings highlight the significant therapeutic potential of MRTX1133, particularly in combination with standard chemotherapy, for the clinical management of KRASG12D-mutant PDAC patients."

Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CASP3 • CDKN2A • KRAS • MIA • SMAD4 • TP53

Preclinical efficacy of the combination of MEK inhibitor plus KRAS G12D inhibitor for non-small cell lung cancer with KRAS G12D (AACR 2025) - "Although no phosphorylation of receptor tyrosine kinases that could be combination drug candidates were observed, several MEK inhibitors, such as trametinib, selumetinib and binmetinib, enhanced the efficacy of MRTX1133 in cell viability assays. The combination of trametinib with MRTX1133 suppressed tumor growth compared to MRTX1133 monotherapy with tolerable toxicity in KRAS G12D-mutated NSCLC in vivo models. In conclusion, our findings indicate that the preclinical efficacy of MRTX1133 monotherapy was limited for NSCLC with KRAS G12D, and therapeutic potential of MEK inhibitors in combination with MRTX1133."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Switch II pocket inhibitor allosterically freezes KRASG12Dnucleotide-binding site and arrests the GTPase cycle. (PubMed, J Mol Biol) - "Taken together, MRTX1133 allosterically 'freezes' the KRASG12D nucleotide-binding site conformation, arresting the canonical GTPase cycle of this oncogenic mutant. This provides a framework for understanding the mechanisms-of-action of SII-P-directed inhibitors and how tumours may acquire resistance."

Journal • Oncology • BRAF • KRAS

Multimetric MRI Captures Early Response and Acquired Resistance of Pancreatic Cancer to KRAS Inhibitor Therapy. (PubMed, Clin Cancer Res) - "Multiparametric MRI provides early biological insights of cancer and stromal response to KRASi treatment and sets the stage for testing the utility of these clinically ready MRI methods in patients receiving KRASi therapy."

Journal • Preclinical • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Oral and selective ribonucleotide reductase (RNR) inhibitor, BBI-825, suppresses acquired resistance to mutant-specific, pan, and multi-RAS targeting inhibitors (AACR 2025) - P1 | "In this preclinical study, we sought to understand whether BBI-825 broadly antagonizes acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of tumor models.We tested the ability of BBI-825 to prevent or delay development of acquired resistance to RAS targeting in a panel of KRASG12D/C/V driven tumor cell lines when used in combination with mutant specific KRASG12D (MRTX-1133, RMC-9805), KRASG12C (adagrasib, sotorasib), pan-KRAS (BI-2493), and multi-RAS (RMC-6236) inhibitors. Overall, we found that BBI-825 successfully antagonizes the development of acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of preclinical models. These findings support clinical investigation of BBI-825 in combination with mutant-specific, pan, and multi-RAS inhibitors to prevent or delay resistance and prolong duration of response."

Preclinical • Oncology • Solid Tumor • KRAS

Identifying novel mechanisms of resistance to KRAS-inhibitors in NSCLC (AACR 2025) - "Recent breakthroughs, however, have led to the development of covalent inhibitors such as Sotorasib (AMG510) and Adagrasib (MRTX849), which specifically target the KRAS G12C mutation and have received FDA approval following successful clinical trials...Proteomic profiling using RPPA analysis has identified significant changes in protein expression, with the YAP/TEAD1 and the PDK1 pathways consistently upregulated in cells resistant to MRTX849 (G12Ci), MRTX1133 (G12Di) and the pan-RAS inhibitor BI3706674...We are also trying to understand the molecular crosstalk between the PDK1 and YAP1/TEAD signaling pathways to functionally induce or maintain resistance to MRTX1133. Achieving the objectives of this research project will be instrumental in addressing the critical challenge of overcoming resistance to KRAS inhibitors and enhancing their effectiveness in clinical applications."

Late-breaking abstract • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • PDK1 • TEAD1 • YAP1

Integrative analysis of acquired drug resistance to KRAS(G12D) inhibitors (AACR 2025) - "Novel therapeutic approaches such as RAS(ON) inhibitors like RMC-6236 or specific KRAS(G12D) PROTAC degraders can significantly inhibit cell proliferation in vitro not only in MRTX1133 acquired resistance but also in adagrasib resistance models. Complex transcriptomic reorganization shows the upregulation of CD24 -a potential cancer stem cell related gene- and the epithelial to mesenchymal signature highlight the difficulty to target drug resistant cells. These findings emphasize the necessity to design combinatorial treatments to prevent and delay the acquisition of drug resistance in KRAS-driven cancers."

Colorectal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • AVEN • CD24 • HRAS • KRAS • NRAS

CD24 promotes development of KRAS-mutant lung adenocarcinoma and response to KRAS-targeted therapy (AACR 2025) - "Analysis of publicly available datasets showed that KRASG12C inhibitor MRTX1257 also increased Cd24a expression in mouse tumor cells with KRAS p.G12C mutations. In syngeneic mice with KrasG12C/+; Tp53R172H/+ KM-LUAD cells, sotorasib treatment enhanced CD24 protein levels in tumors compared to controls...Syngeneic mice treated with MRTX1133 and anti-CD24 antibodies showed greater KM-LUAD reduction than single agents or controls...Similarly, combining KRASG12C inhibitor adagrasib with anti-CD24 antibody in syngeneic mice reduced KM-LUAD growth more than single treatments or controls. Our findings demonstrate that CD24 drives KM-LUAD progression from its earliest stages and contributes to adaptive resistance to KRAS inhibition. Targeting CD24 in combination with KRAS inhibitors, represents a promising strategy for treating and intercepting KM-LUAD."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD24 • GPRC5A • KRAS

Combination of MTA-cooperative PRMT5 inhibitor BMS-986504 and KRAS inhibitors for the treatment of MTAP-deleted KRAS-mutant pancreatic cancer (AACR 2025) - "We validated co-targeting KRAS as a combination strategy and found that combined small molecule inhibition of PRMT5 and G12C/D-mutant KRAS (using adagrasib and MRTX1133, respectively) effectively suppressed MTAP-del PDAC growth in vitro and in vivo. Further, we determined that, while PRMT5 and KRAS regulate distinct transcriptomes, they converge on common pathways governing cancer cell growth and combined inhibition of PRMT5 and KRAS caused marked downregulation of PDAC-essential genes. These findings provide a rationale for combined inhibition of PRMT5 and KRAS to maximize targeted therapies for MTAP-del and KRAS-mutant biomarker-positive PDAC."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MIA • MTAP • PRMT5

A 1st in class pan-RAS inhibitor with robust antitumor activity in PDAC models and advantages over other RAS inhibitors to escape resistance (AACR 2025) - "Growth assays involving direct comparison of ADT-007 with mutant-specific KRASG12C inhibitors (sotorasib), pan-KRAS inhibitors (BI-2865), or other pan-RAS inhibitors (RMC-6236) revealed more complete cancer cell killing by ADT-007. Finally, cancer cell lines resistant to KRASG12C and KRASG12D inhibitors retained complete sensitivity to ADT-007 but showed resistance to MRTX849 and MRTX1133, respectively. These results show the unique advantages of ADT-1004 over mutant-specific KRAS, pan-KRAS, and other pan-RAS inhibitors to escape resistance that limits the efficacy of RAS inhibitors FDA-approved or in clinical trials."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BRAF • EGF • KRAS

Targeting XPO1 to enhance the durability of response of MRTX1133 in pancreatic ductal adenocarcinoma (AACR 2025) - "This is the first study showing that KPT8602 treatment can overcome resistance to MRTX1133 and synergistically augment the antitumor effects of MRTX1133 in PDAC preclinical models. This combination regimen can potentially prevent or delay drug resistance by making it feasible to achieve a more durable response at a lower dose of KRASG12D inhibitor."

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

Profiling Ras inhibitors for effects on GTP hydrolysis using the Transcreener GDP assay (AACR 2025) - "MRTX1133, which binds noncovalently to GDP-bound KRas G12D, inhibited the G12D mutant with an IC50 of 8.4 nM, and was less potent with the G12V and WT enzymes; IC50 = 48 nM and 69 nM, respectively. We note that these GTPase assays require nanomolar concentrations of protein, and therefore cannot be used to accurately determine the potency of covalent inhibitors, such as sotorasib, that bind with picomolar affinity. However, for non-covalent inhibitors, such as MRTX1113 and BI-2865, measuring GTPase activity is a robust approach for selectivity profiling and may yield mechanistic insights different from those gleaned from guanine nucleotide binding/release assays or biophysical methods, e.g. SPR."

Oncology • KRAS

A precision polypharmacology approach to co-target EGFR and PI3 kinase: the power of structure-based drug design to generate therapeutic agents with versatility in multiple combination settings (AACR 2025) - "In vivo studies were carried out in KRAS G12D mutant tumor-bearing mice showing that treatment with MTX-531 led to striking enhancement of KRAS inhibitor (MRTX-1133) activity against a broad spectrum of gastrointestinal cancers (pancreatic, colorectal, gastric) as evidenced by a high incidence of durable tumor regressions. Collectively, these studies demonstrate the versatility of MTX-531 to serve as the backbone of combination regimens across diverse modalities encompassing treatment with targeted therapies, radiation, or immune checkpoint inhibitors. Based on its promising preclinical profile, MTX-531 represents a first-in-class approach to precision polypharmacology that demonstrates the power of rational structure-based drug design to target multiple resistance drivers in a single molecule."

IO biomarker • Breast Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • EGFR • KRAS