salirasib (KD 032) / Ono Pharma, Advanz Pharma, Sanofi - LARVOL DELTA

CAMK2B Impacts the Proliferation, Invasion, and Migration of Glioma Cells via the Ras/Raf/MEK/ERK Signaling Pathway. (PubMed, Oncol Res) - "Notably, these effects were reversed through the application of the Rat Sarcoma viral oncogene homolog (Ras) pathway inhibitor, Salirasib. Western blot analysis revealed that knockdown of CAMK2B led to activation of the Ras/Rapidly Accelerated Fibrosarcoma (Raf)/Mitogen-activated protein kinase kinase (MEK)/Extracellular signal-regulated kinase (ERK) signaling pathway in glioma cell lines, whereas overexpression of CAMK2B resulted in the suppression of this pathway. CAMK2B inhibits glioma proliferation, invasion, and migration through the Ras/Raf/MEK/ERK signaling pathway."

Journal • Brain Cancer • CNS Tumor • Fibrosarcoma • Glioma • High Grade Glioma • Oncology • Solid Tumor

Targeting c-Myc enhances immunotherapy efficacy in combination with Ras inhibitor in triple-negative breast cancer. (PubMed, Clin Transl Med) - "In summary, our investigation identifies a molecular vulnerability in c-Myc-driven TNBC, where Ras inhibition reinforces c-Myc-targeted therapy and potentiates immune checkpoint blockade, presenting a promising strategy to improve immunotherapy efficacy in TNBC."

IO biomarker • Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • MCM2 • MYC

Identification of novel pan-KRAS mutation inhibitor shows significant efficacy in pancreatic cancer with no toxicity, offering hope beyond current therapies (AACR 2025) - "Although the FDA has approved two KRAS inhibitors (Sotorasib and Adagrasib) for lung cancer, these drugs specifically target the KRAS-G12C mutation, found in only 2% of PDAC cases...Clonogenic assays demonstrated that 3E was more effective than Adagrasib and Salirasib (a non-specific RAS inhibitor in Phase II trials) at inhibiting PDAC cell growth...These findings suggest that 3E is a promising therapeutic candidate for KRAS-driven PDAC and other cancers. Its superior efficacy over FDA-approved KRAS inhibitors and synergy with gemcitabine support its clinical potential as a novel treatment approach for this aggressive cancer."

Clinical • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Neutrophil Extracellular Trap Formation Model Induced by Monosodium Urate and Phorbol Myristate Acetate: Involvement in MAPK Signaling Pathways. (PubMed, Int J Mol Sci) - "They include the Ras inhibitor Salirasib, Raf inhibitor Vemurafenib, ERK inhibitor PD98059, and p38 MAPK inhibitor SB203580, as well as NADPH oxidase inhibitor DPI and neutrophil elastase inhibitor Alvelestat. These data indicated that the activation of a signaling pathway involving Ras-Raf-ERK, which is dependent on ROS, is crucial for the induction of NET formation by MSU and PMA. Given the involvement of NETs in multiple pathologies, our findings could potentially serve as molecular targets for the intervention and treatment of crystal-related diseases, especially for gout."

Journal • Gout • Inflammation • Inflammatory Arthritis • Rheumatology • CXCL8 • ELANE

Synergistic two-step inhibition approach using a combination of trametinib and onvansertib in KRAS and TP53-mutated colorectal adenocarcinoma. (PubMed, Biomed Pharmacother) - "To determine the sensitivity of KRAS or/and TP53-mutated cancer to KRAS, MEK1, or PLK1-targeted therapy, the inhibitors salirasib, trametinib, volasertib, and onvansertib were used in COAD cells with different KRAS and TP53 status. This treatment induced G1 and G2/M arrest, respectively, and showed the strongest synergistic effect in KRAS and TP53-mutated SW48 cells expressing mutant KRASG13D and transduced with TP53 shRNA, ultimately leading to apoptotic cell death. These effects are attributed to two-step inhibition mechanism that blocks the MAPK signaling pathway and disrupts mitosis in KRAS and TP53-mutated COAD cells."

Journal • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • KRAS • TP53

Salirasib Inhibits the Expression of Genes Involved in Fibrosis in Fibroblasts of Systemic Sclerosis Patients. (PubMed, Immun Inflamm Dis) - "Considering salirasib significantly reduced the expression of genes related to the fibrosis process and α-SMA gene and protein expression, and given significant upregulation of MMP1 by salirasib, it can be considered as a new curative strategy for fibrotic diseases like SSc."

Journal • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • ACTA2 • COL1A1 • COL1A2 • CTGF • MMP1 • TGFB1

Loss of HNRNPU in Skeletal Muscle Increases Intramuscular Infiltration of Ly6C Positive Cells, leading to Muscle Atrophy through Activation of NF-κB Signaling. (PubMed, Adv Biol (Weinh)) - "Treatment with salirasib, to inhibit proliferation of immune cells, prevents muscle atrophy in muscle-specific hnRNPU knock out mice, indicating that immune cell infiltration plays causal role in muscle atrophy of hnRNPU knock out mice. Overall, the findings suggest that loss of hnRNPU triggers muscle inflammation and activates NF-κB signaling in a cell-autonomous manner, culminating in muscle atrophy."

Journal • Inflammation • Muscular Atrophy

In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables ATAD3A gene depletion to enhance RAS-targeted therapy (AACR 2024) - "Most interestingly, the addition of LNP-sgATAD3A to the RAS inhibitor salirasib potentiated anticancer activity for HNSCC compared with the efficacy resulting from single-arm treatment. These novel and significant findings demonstrate a novel approach to inhibiting ATAD3A in tumor cells and provide a possible therapeutic strategy to enhance the success of multimodality therapy in cancer patients."

Preclinical • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Tongue Carcinoma • VDAC1

Prevention of Protease-Induced Degradation of Desmoplakin via Small Molecule Binding. (PubMed, J Pers Med) - "We find that several molecules, including sodium dodecyl sulfate, palmitoylethanolamide, GW0742, salirasib, eprosarten mesylate, and GSK1838705A prevent wildtype and disease-variant-carrying DSP protein degradation in the presence of both trypsin and calpain without altering protease function. Molecular dynamic simulations of DSP-drug complexes suggest that some long hydrophobic molecules can bind in a shallow hydrophobic groove that runs alongside the protease cleavage site. Identification of these compounds lays the groundwork for pharmacological treatment for individuals harboring these hypersensitive DSP variants."

Journal • Cardiomyopathy • Cardiovascular • Immunology • Targeted Protein Degradation

Heat stress induces ferroptosis of porcine Sertoli cells by enhancing CYP2C9-Ras- JNK axis. (PubMed, Theriogenology) - "Salirasib, a specific inhibitor of Ras, significantly elevated the cell viability, whereas reduced the level of intracellular ROS and inhibited the phosphorylation of JNK, and alleviated heat stress-induced ferroptosis in porcine Sertoli cells...These results indicate that heat stress can induce ferroptosis in Sertoli cells by increasing the expression of CYP2C9 and the content of EETs, which in true activates the Ras-JNK signaling pathway, but there is no feedback from Ras-JNK signaling to the expression of CYP2C9. Our study finds a novel heat stress-induced cell death model of Sertoli cells as well as providing the therapeutic potential for anti-ferroptosis."

Journal • Preclinical • CYP2C9 • GPX4 • TFRC

Lipophilic modification of salirasib modulates the antiproliferative and antimigratory activity. (PubMed, Bioorg Med Chem) - "Three analogues with specific antimigratory activity were identified with differential structural features being interesting starting points on the development of new antimetastatic agents. The antiproliferative and antimigratory effects observed suggest that modifying the thiol aliphatic/prenyl substituents can modulate the activity."

Journal • Oncology • Solid Tumor

Upregulation of KLHL17 promotes the proliferation and migration of non-small cell lung cancer by activating the Ras/MAPK signaling pathway. (PubMed, Lab Invest) - "Moreover, treatment of tumor cells with Ras inhibitor salirasib prevented KLHL17-induced Ras/MAPK activity as well as tumor proliferation and migration...This study elucidates the role of KLHL17 in the development and progression of NSCLC using clinical samples and NSCLC cell lines. The results show that upregulated KLHL17 in NSCLC promotes the proliferation and migration of tumor by activating Ras/MAPK signaling pathway, and suggest that KLHL17 may be a novel therapeutic target for the treatment of NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • CCND1 • CDK4 • MMP2 • RHOA

Cross-talk between the RAS-ERK and mTOR signalings-associated autophagy contributes to tripterygium glycosides tablet-induced liver injury. (PubMed, Biomed Pharmacother) - "RAS-ERK-mTOR cross-talk may play a crucial role in TGT-induced hepatocyte autophagy, offering a promising target for developing novel therapeutics to combat TGT-induced hepatotoxicity."

Journal • Hepatology • Immunology • Inflammatory Arthritis • Liver Failure • Ophthalmology • Rheumatoid Arthritis • Rheumatology

Aquaporin water channels affect the response of conventional anticancer therapies of 3D grown breast cancer cells. (PubMed, Biochem Biophys Res Commun) - "Therefore, we took a systematic approach to test how AQP1, AQP3 and AQP5, which are often over-/ectopically expressed in breast cancer, affect total viability of 3-dimensional (3D) breast cancer cell spheroids when treated with the conventional anticancer chemotherapies Cisplatin, 5-Fluorouracil (5-FU) and Doxorubicin, a Combination of the three drugs as well as the Combination plus the Ras inhibitor Salirasib. Thus, this study supports a significant role of AQPs in the response to conventional chemotherapies. Evaluating the role of individual proteins that contribute to resistance to chemotherapies is essential in advancing personalized medicine in breast carcinomas."

Journal • Breast Cancer • Oncology • Solid Tumor • AQP1

Upregulation of KLHL17 promotes the proliferation and migration of non-small cell lung cancer by activating the Ras/MAPK signaling pathway. (PubMed, Lab Invest) - "Moreover, treatment of tumor cells with Ras inhibitor salirasib prevented KLHL17-induced Ras/MAPK activity as well as tumor proliferation and migration. These results suggest that upregulated KLHL17 in NSCLC promotes the proliferation and migration of tumor by activating Ras/MAPK signaling pathway. Therefore, KLHL17 may be a novel therapeutic target for the treatment of NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • CCND1 • CDK4 • MMP2 • RHOA

The role of endothelin and RAS/ERK signaling in immunopathogenesis-related fibrosis in patients with systemic sclerosis: an updated review with therapeutic implications. (PubMed, Arthritis Res Ther) - "Furthermore, Salirasib is a synthetic small molecule that is able to inhibit all Ras forms. Therefore, it can be used as a potent therapeutic factor for fibrotic disorders. So, this review discusses the role of TGF-β/ET-1/Ras signaling and their involvement in SSc pathogenesis, particularly in its fibrotic situation."

Journal • Review • Developmental Disorders • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • CTGF • EDN1 • TGFB1

γ-Tocotrienol inhibition of metastatic phenotypic behavior is associated with a decrease in galectin-3 expression and distribution in the highly malignant mouse +SA & TS/A mammary tumor cells (AACR 2022) - "Computer-aided molecular modeling studies compared anticancer agents, salirasib and γ-tocotrienol, with the active site of galectin-3 and β-lactose (a known ligand)...In TS/A cells, 6-15 μM tocotrienol induced a dose-responsive increase in doxorubicin staining inside the nucleus...These findings also suggest that γ-tocotrienol may provide significant benefits in the prevention and/or treatment of metastatic breast cancer. This study was supported in part by funding from the Louisiana Cancer Foundation."

Preclinical • Breast Cancer • Oncology • Solid Tumor • FN1 • LGALS3

Suppression of Cholangiocarcinoma Cell Growth and Proliferation by Atractylodes lancea (Thunb) DC. through ERK-Signaling Cascade. (PubMed, Asian Pac J Cancer Prev) - "The ERK signaling cascade and downstream molecules are potential targets of action of AL in CCA."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor • MAPK1

Oleic acid alleviates LPS-induced acute kidney injury by restraining inflammation and oxidative stress via the Ras/MAPKs/PPAR-γ signaling pathway. (PubMed, Phytomedicine) - "In a word, OA could alleviate AKI by restraining inflammation and oxidative stress via regulating the Ras/MAPKs/PPAR-γ signaling pathway, phenylalanine metabolism, purine metabolism, sphingolipid metabolism and taurine and hypotaurine metabolism, which might be a useful strategy for treating AKI."

Journal • Acute Kidney Injury • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease

[VIRTUAL] γ-Tocotrienol inhibition of metastatic phenotypic behavior is associated with a decrease in galectin-3 expression and distribution in the highly malignant mouse +SA & TS/A mammary tumor cells (AACR 2021) - "Computer-aided molecular modeling studies were carried out within the active site of galectin-3 based on the crystal structure (5EXO) obtained from the protein data bank with a known ligand, and anticancer agents (salirasib, γ-tocotrienol, and β-lactose) galectin-3 docking scores and amino acid interactions were determine...In summary, these results demonstrate for the first time that γ-tocotrienol treatment inhibits extracellular galectin-3 expression and disrupts galectin-3 carbohydrate binding and activation of +SA and TS/A mammary tumor cells. These findings also suggest that γ-tocotrienol may provide significant benefits in the prevention and/or treatment of metastatic breast cancer."

Preclinical • Breast Cancer • Oncology • Solid Tumor • FN1

A screen of FDA-approved drugs identifies inhibitors of protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3). (PubMed, Sci Rep) - "In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CXR motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function."

FDA event • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PTP4A3

Inhibition of ERAD synergizes with FTS to eradicate pancreatic cancer cells. (PubMed, BMC Cancer) - "Our study reveals a critical role for ERAD in therapeutic response of FTS and points to the modulation of UPR as a novel approach to improve the efficacy of FTS in PDAC treatment."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • KRAS

[VIRTUAL] Biology of KRAS Targeting Agents (IASLC-WCLC 2020) - "Salirasib, farnesyl thiosalicylic acid, inhibits prenylated protein methyltransferase (PPMTase) with potent in vitro activity, including against KRAS; however, failed in a phase II trial12...For example, the phase 3 trial of MEK inhibitor selumetinib 13 did not show its benefit...Based on these experiments, abemaciclib, a CDK4/6 inhibitor, plus erlotinib was compared with erlotinib in patients with KRAS mutation in a phase III trial...Aguirre AJ, et al.: Cold Spring Harb Perspect Med 8, 2018 16. Goldman JW, et al.: Front Oncol 10:578756, 2020"

IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology • Solid Tumor • BIRC5 • CDKN2A • CDKN2B • GATA2 • HRAS • KRAS • NF1 • NOS3 • NRAS • PLK1 • RASGRP1 • SYK • TP53 • TTF-1 • WT1

Celecoxib combined with salirasib strongly inhibits pancreatic cancer cells in 2D and 3D cultures. (PubMed, Int J Med Sci) - "This combination strongly inhibited NF-κB activity and reduced pAkt and Bcl-2 levels in Panc-1 cells. SAL in combination with CEL may represent a new approach for effective inhibition of pancreatic cancer."

Journal • Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • BCL2 • CASP3

Overexpression of FNTB and the activation of Ras induce hypertrophy and promote apoptosis and autophagic cell death in cardiomyocytes. (PubMed, J Cell Mol Med) - "In addition, salirasib (a Ras farnesylcysteine mimetic) can alleviate the hypertrophic phenotype of cardiomyocytes and inhibit the up-regulation of apoptosis and autophagy flux induced by FNTB overexpression. These results suggest that FTase may have a potential role in future treatment strategies to limit the adverse consequences of cardiac hypertrophy, cardiac dysfunction and heart failure."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • FNTB