ADT-1004 / Auburn University, ADT Pharma - LARVOL DELTA

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

ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma. (PubMed, Mol Cancer) - "ADT-1004 has strong antitumor activity in aggressive and clinically relevant PDAC models with unique selectivity to block RAS-mediated signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC."

Journal • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD4 • CD8 • KRAS

ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma (Mol Cancer) - "ADT-1004 potently blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity with target engagement and reduced activated RAS and ERK phosphorylation. In addition, ADT-1004 suppressed tumor growth in PDX PDAC models with KRASG12D, KRASG12V, KRASG12C, or KRASG13Q mutations and increased CD4+ and CD8+ T cells in the TME consistent with exhaustion and increased MHCII+ M1 macrophage and dendritic cells."

Preclinical • Pancreatic Ductal Adenocarcinoma

Preclinical Development of a Novel Pan-RAS Inhibitor Against Relapsed/Refractory Multiple Myeloma (ASH 2024) - "Furthermore, the in vitro efficacy of ADT-007 was significantly better (nM vs. µM IC50) than cyclorasin B4-27, a bicyclic peptidyl that has been reported as a potent pan-RAS inhibitor against several other cancers, and RMC-6236, a multi-selective noncovalent RAS(on) inhibitor which is in clinical trial for patients with advanced solid tumors harboring G12X, G13X, and Q61X mutations. Next, we plan to evaluate the antitumor activity of ADT-1004 in mouse xenograft models of human myeloma using immunocompromised mice. Our research will lay the groundwork for future development efforts needed to advance ADT-1004 to clinical trials involving patients with RRMM."

Preclinical • Hematological Malignancies • Hepatology • Multiple Myeloma • Oncology • Pancreatic Cancer • Solid Tumor • ANXA5 • CASP3 • CASP7 • IKZF1 • IKZF3 • IRF4 • KRAS • MYC • NRAS

A novel pan-RAS inhibitor (ADT-1004) with superior efficacy over mutation-specific KRAS inhibitors in mouse models of pancreatic cancer (EORTC-NCI-AACR 2024) - "ADT-1004, sotorasib, or adagrasib was administered orally (40mg/kg) 5x/week for 4 weeks. In vitro growth inhibition by ADT-007 was very potent in mutant KRAS cells (IC50 = 2 nM KRASG12C MIA PaCa-2 PDAC), but also highly selective (RASWT BxPC3 PDAC cells IC50 = 2500 nM). Growth of KRAS-mutant PDAC tumors was suppressed by ADT-1004 and was accompanied by inhibition of signaling downstream of RAS (MAPK/AKT). ADT-1004 demonstrated superiority in direct comparison with KRASG12C specific inhibitors in models of resistance. These results show clinically relevant advantages of a pan-RAS inhibitor to treat PDAC and other RAS driven cancers with a spectrum of mutations in all RAS isoforms."

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

ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma. (PubMed, bioRxiv) - "ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRAS G12C inhibitors. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC."

Journal • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD4 • CD8 • KRAS

[PREPRINT] ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma (bioRxiv) - "As evidence of target engagement and tumor specificity, ADT-1004 inhibited activated RAS and ERK phosphorylation in PDAC tumors at dosages approximately 10-fold below the maximum tolerated dose and without discernable toxicity. ADT-1004 inhibited ERK phosphorylation in PDAC tumors. In addition, ADT-1004 blocked tumor growth and ERK phosphorylation in PDX PDAC models with KRASG12D, KRASG12V, KRASG12C, or KRASG13Q mutations. ADT-1004 treatment increased CD4+ and CD8+ T cells in the TME consistent with exhaustion and increased MHCII+ M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRASG12C inhibitors."

Preclinical • Preprint • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Efficacy advantages of a novel pan-RAS inhibitor, ADT-1004, over mutant-specific KRAS inhibitors for suppressing pancreatic tumor growth in murine models (AACRPanCa 2024) - "Sotorasib and adagrasib KRASG12C inhibitors were administered at the same dose, route, and schedule as ADT-1004. ADT-1004 inhibited tumor growth of KRAS mutant PDAC tumors by blocking activated RAS to disrupt downstream MAPK/AKT signaling. Side-by-side comparisons reveal antitumor efficacy advantages of ADT-1004 over mutant-specific KRAS inhibitors. These results highlight the promise of ADT-1004 for treatment of PDAC and other RAS-driven cancers by addressing the complex genetic landscape of many cancers and limitations from resistance to mutant specific KRAS inhibitions."

Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MIA

A Novel Pan-RAS Inhibitor, ADT-1004, with Efficacy and Tolerability Advantages Over Other RAS Inhibitors to Suppress Tumor Growth in Multiple Mouse Models of Pancreatic Cancer (DOT 2024) - No abstract available

Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

A potent and selective pan-RAS inhibitor, ADT-1004, targeting complex KRAS mutations for pancreatic cancer. (ASCOBT 2024) - "ADT-1004 inhibited tumor growth of KRAS mutant PDA tumors by targeting activated RAS to disrupt downstream MAPK/AKT signaling. The results highlight the promise of ADT-1004 as a novel pan-RAS inhibitor and open new strategies for addressing the complex genetic landscape of PDAC and other RAS driven cancers."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

A potent and selective pan-RAS inhibitor, ADT-1004, targeting complex KRAS mutations for pancreatic cancer. (ASCO 2024) - "ADT-1004 inhibited tumor growth of KRAS mutant PDA tumors by targeting activated RAS to disrupt downstream MAPK/AKT signaling. The results highlight the promise of ADT-1004 as a novel pan-RAS inhibitor and open new strategies for addressing the complex genetic landscape of PDAC and other RAS driven cancers."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

ADT-1004: A promising pan-RAS inhibitor for targeting KRAS mutations in pancreatic ductal adenocarcinoma (AACR 2024) - "Unfortunately, existing drugs targeting the RAS family, like sotorasib, exclusively address the KRAS-G12C mutation, mainly found in NSCLC. These results highlight the promise of ADT-1004 as a potential breakthrough for treating PDAC. This novel pan-RAS inhibitor demonstrates potent inhibition of PDAC growth, irrespective of the specific KRAS mutation. Furthermore, it shows an excellent safety profile, with profound tumor regression and no impact on body weight in animal models."

Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Novel Pan-RAS inhibitor ADT-007: A unique mechanism of antitumor selectivity in pancreatic and colorectal carcinoma models (AACR 2024) - "Multiple types of RAS mutations activate RAS isoforms, HRAS, NRAS, or KRAS, that drive oncogenic signaling leading to uncontrolled cell proliferation and tumor development. An orally bioavailable prodrug of ADT-007 (ADT-1004) is well tolerated in vivo, and produced sustained concentrations of ADT-007 well above IC50 values in plasma and even higher levels in tumors. Daily oral administration of ADT-1004 significantly inhibited RAS signaling and tumor growth in orthotopic and PDX mouse models of pancreatic cancer."

Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • HRAS • KRAS • NRAS

Antitumor activity of 1st-in-class pan-RAS inhibitor ADT-1004 in mouse models of pancreatic ductal adenocarcinoma (AACR 2023) - "ADT-1004 represents a 1st-in-class pan-RAS inhibitor with potential advantages over mutant-specific KRAS inhibitors for greater efficacy and ability to avert mechanisms of resistance. These data support future clinical trials of ADT-1004 as a monotherapy for the treatment of patients with PDA regardless of the underlying mutation."

Late-breaking abstract • Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS