CB-5083 / Cleave Therap - LARVOL DELTA

FGD5 regulates PGK1 ubiquitination to synergize with 2-deoxy-D-glucose in pancreatic ductal adenocarcinoma. (PubMed, Oncogene) - "Pancreatic ductal adenocarcinoma (PDAC) exhibits profound metabolic plasticity that underlies its aggressive growth and therapeutic resistance. Pharmacological perturbation with CB-5083 attenuates FGD5-PGK1-associated proteostasis readouts, whereas 2-DG inhibits glycolytic flux and lactate-associated H3K18la. Together, CB-5083 and 2-DG cooperate to suppress PDAC growth by coupling perturbation of the FGD5-PGK1-associated proteostasis axis with glycolytic inhibition."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Targeted Protein Degradation • PGK1

Cryo-EM-guided subtractive optimization of a novel VCP/p97 inhibitor. (PubMed, IUCrJ) - "Our approach overcomes the liability in the clinical-stage compound CB-5083 where Phase I studies showed off-target activity of CB-5083 for the enzyme PDE6...We refer to this approach as `subtractive optimization' because we are leveraging our ability to determine both on-target and off-target cryo-EM structures to guide the medicinal chemistry campaign to enable more targeted compound design. While this strategy is not possible in all cases, the use of cryo-EM to tune on-site binding while eliminating off-target binding could be a generally applicable strategy for informing molecular design and accelerating small-molecule drug discovery."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Valosin-Containing Protein Contributes to Plexiform Neurofibroma Formation and Represents a Novel Therapeutic Target. (PubMed, Cells) - "In vivo treatment with CB-5083 in Nf1fl/fl;DhhCre PNF mice significantly inhibited cell proliferation, increased cell apoptosis and reduced PNF volume. The combination with a MEK inhibitor did not increase efficacy compared to the single agent, supporting the hypothesis that VCP functions in parallel to, and may be modulated by, RAS-MAPK signaling under stress or oncogenic conditions. The significant effects of VCP inhibition in this pre-clinical study suggest a potential novel therapy for patients with PNFs."

Journal • Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor • Targeted Protein Degradation • Transplantation • NF1 • RUNX1 • VCP

Pharmacological Inhibition of Valosin-Containing Protein (VCP) Triggers Cardiac Hypertrophy and Heart Failure in Vivo. (PubMed, Mol Cell Biol) - "This study examines the effects of pharmacological Vcp inhibition in zebrafish embryos using CB-5083, a selective Vcp ATPase inhibitor...Furthermore, Vcp inhibition was associated with markers of disrupted proteostasis, suggesting UPS dysfunction and ER stress activation. These findings establish a zebrafish model of VCP-related cardiomyopathy, highlight its role in cardiac proteostasis and hypertrophic remodeling, and provide novel insights into disease mechanisms and potential therapeutic targets."

Journal • Preclinical • Cardiomyopathy • Cardiovascular • CNS Disorders • Congestive Heart Failure • Heart Failure • Myositis • Oncology • Targeted Protein Degradation

Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension. (PubMed, Genet Med) - "We identify the prevalent genetic cause of pulmonary hypertension in AOS and highlight a potential therapeutic approach."

Journal • Cardiovascular • Hypertension • Proteinopathy • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • VCP

Cryo-EM-guided enhancement of target selectivity of a novel p97 inhibitor for treating multiple myeloma and acute myeloid leukemia (AACR 2024) - "In this model, where GND-135 was administered IP (40 mg/kg QD) and CB-5083 was administered orally (40 mg/kg QD) the compounds showed statistically comparable efficacy, which was differentiated from untreated control. Thus, GND-135 is a novel p97 inhibitor lead compound with on-target selectivity powered by cryo-EM driven rational drug design."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

Inhibition of VCP in an in vivo model of metastatic melanoma selected based on a predictive biomarker demonstrates tumor reduction (AACR 2025) - "Hypotheses derived from in silico predictions were validated using various forms of VCP loss including pharmacological inhibition using a phase 1 VCPi, CB5083, as a reference compound, siRNA and by conditional knockout...Targeting a common essential gene such as VCP is associated with a narrow therapeutic index, however, we have demonstrated efficacy using a relatively low dose of 50 mg/kg . Taken together, we are proposing a patient stratification strategy based on the identification of a predictive biomarker from an in silico screen."

Metastases • Preclinical • Melanoma • Oncology • Solid Tumor • MITF

Regulation of ER-Resident Transcription Factor NFE2L1 in HEK293 Cells. (PubMed, Biol Pharm Bull) - "NFE2L1 protein expression in wild-type HEK293 cells was negligible, but MG132/bortezomib treatment induced Endo H-resistant two bands...Treatment with the valosin containing protein (VCP) inhibitor CB-5083 increased NFE2L1 expression, but deficiencies in other ERAD-associated factors (ER degradation-enhancing α-mannosidase-like protein 2 (EDEM2), thioredoxin domain-containing protein 11 (TXNDC11), gp78, ring finger protein 5 (RNF5), ring finger protein 185 (RNF185), and USP19) did not affect its expression...Therefore, we constructed NFE2L1 genes with mutations in the site where NFE2L1 is cleaved by DDI2 and in the four asparagine residues where N-glycosylation occurs, and found that the high molecular weight form, especially a hypoglycosylated mutant, tended to be more unstable. Taken together, this study using several ERAD disordered models shows that the regulation of NFE2L1 is different in some ways from the regulation of CREB3/ATF6 family, and these findings..."

Journal • ATF6 • TXNDC11 • USP19

Identifying metabolic vulnerabilities of recurrent IDH1-R132H mutant glioma by high throughput screening (SNO 2025) - "Notable target pathways include folate metabolism and de novo thymidylate synthesis (methotrexate, raltitrexed, 5-FU), p97 AAA ATPase/VCP chaperone (CB-5083, ML240, eeyarestatin I), mevalonate pathway (Ro 48-8071 fumarate, atorvastatin calcium), and the BCL-2 family (Navitoclax, ABT-737). We are validating these drugs across a panel of patient-derived IDH-mutant gliomasphere models, and examining the combinatorial effects of these agents with vorasidenib and CDK4/6 inhibitors. Our results provide insight into important metabolic pathway dependencies in recurrent IDH1-R132H mutant gliomas that have targeting potential."

IO biomarker • Brain Cancer • Glioma • Oligodendroglioma • Solid Tumor • BCL2 • IDH1 • NAMPT

Identifying metabolic vulnerabilities of recurrent IDH1-R132H mutant glioma by high throughput screening (WFNOS 2025) - "Notable target pathways include folate metabolism and de novo thymidylate synthesis (methotrexate, raltitrexed, 5-FU), p97 AAA ATPase/VCP chaperone (CB-5083, ML240, eeyarestatin I), mevalonate pathway (Ro 48-8071 fumarate, atorvastatin calcium), and the BCL-2 family (Navitoclax, ABT-737). We are validating these drugs across a panel of patient-derived IDH-mutant gliomasphere models, and examining the combinatorial effects of these agents with vorasidenib and CDK4/6 inhibitors. Our results provide insight into important metabolic pathway dependencies in recurrent IDH1-R132H mutant gliomas that have targeting potential."

IO biomarker • Brain Cancer • Glioma • Oligodendroglioma • Oncology • Solid Tumor • BCL2 • IDH1 • NAMPT

Functional pH-Responsive Nanoparticles for Immune Reprogramming in MSS Colorectal Cancer via ER Stress-Induced Proteostasis Disruption, PD-L1-Targeting miRNA, and TLR7 Activation. (PubMed, Pharmaceutics) - "To overcome these barriers, a pH-responsive solid lipid nanoparticle (SLN) system was engineered to co-deliver CB-5083 (a VCP/p97 inhibitor), miR-142 (a PD-L1-targeting microRNA), and imiquimod (R, a TLR7 agonist) for spatially confined induction of endoplasmic reticulum stress (ERS) and immune reprogramming in MSS CRC. Biodistribution analysis confirmed tumor-preferential accumulation with minimal off-target exposure, and biosafety profiling demonstrated low systemic toxicity. This TME-responsive nanoplatform therefore integrates ERS induction, checkpoint modulation, and cytokine suppression to overcome immune exclusion in MSS CRC, representing a clinically translatable strategy for chemo-immunotherapy in immune-refractory tumors."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • ATF4 • CD4 • CD8 • CXCL1 • EGFR • IL17A • MIR142 • PD-L1 • TLR7

Targeting VCP enhances colorectal cancer therapy through STING stabilization. (PubMed, J Immunother Cancer) - "Our study identifies VCP as a new regulator of STING proteostasis and provides a novel strategy to boost antitumor immunity by pharmacologically increasing ER-resident STING via VCP inhibition, offering a clinically actionable avenue to improve CRC therapy."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CD8 • CD86 • CGAS • STING

Harnessing p97/VCP: A Transformative AAA+ ATPase Target for Next-Generation Cancer Therapeutics. (PubMed, Cancers (Basel)) - "This review explores p97's molecular structure, diverse cellular roles, and clinical potential with a particular focus on CB-5083 and CB-5339, the only p97 inhibitors to date that have advanced into clinical trials. We discuss their mechanisms of action, clinical trial outcomes, and the transformative potential of rational combination strategies to maximize their therapeutic potential. By integrating foundational biological insights with translational perspectives, we highlight p97 as a precision target for cancer treatment."

Journal • Review • Oncology • Targeted Protein Degradation

Dual Targeting using SAHA and Diethyldithiocarbamate (DDC)-Metal Complexes Augments Sodium Iodide Symporter Function in Thyroid and Breast Cancer (ATA 2025) - "SAHA (vorinostat) was used as a candidate HDACi. Results Clinically trialled VCP inhibitors CB-5083 and CB-5339 markedly induced 125I uptake in multiple thyroid and breast cancer cells, as well as in human primary thyrocytes (up to 4.0-fold; P<0.001)...Biodistribution studies revealed no differences in 99mTc uptake in other major tissues, or any change in body weight. Conclusion Our study identifies a new combinatorial strategy to stimulate NIS activity in vivo, with potential clinical application for improving radionuclide-based therapies and imaging across multiple cancer settings."

Breast Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma

Antitumor Efficacy of 1,2,4-Triazole-Based VCP/p97 Allosteric Inhibitors. (PubMed, J Med Chem) - "Here, we highlight the optimization of the previously reported 3-thioalkyl-1,2,4-triazol-pyridyl allosteric inhibitor scaffold and identify two compounds (25 and 38) with low-nanomolar biochemical potency, submicromolar cellular inhibition, in vivo effects on biomarkers of VCP inhibition, and antitumor efficacy in mouse xenograft tumor models. Furthermore, compound 38 demonstrated robust inhibition of VCP ATP-site mutant proteins and growth of cells resistant to the known ATP-competitive inhibitor CB-5083."

Journal • Tumor mutational burden • Oncology • Targeted Protein Degradation • TMB

FAT1 Enhances the Sensitivity of Non-Small Cell Lung Cancer to VCP Inhibitors by Regulating the Activation of the Endoplasmic Reticulum Stress Pathway. (PubMed, FASEB J) - "Using data from the PRISM Repurposing drug sensitivity database, we observed that among compounds related to protein homeostasis, the valosin-containing protein (VCP) inhibitor CB-5083 demonstrated the most significant variation in sensitivity among NSCLC cells, categorized according to FAT1 expression levels...Our results suggest that FAT1 regulates the activation of the ER stress pathway through YAP signaling, influencing the susceptibility of NSCLC cells to VCP inhibitors. These insights provide novel perspectives for NSCLC treatment and extend the therapeutic applications of VCP inhibitors in clinical settings."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CDH1 • FAT1

CB-5083 and luteolin synergistically induce the apoptosis of bladder cancer cells via multiple mechanisms. (PubMed, Toxicol Appl Pharmacol) - "Our data suggest that combined treatment with CB-5083 and Lut might be applied to treat BC."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urethral Cancer • Urology • BCL2L1 • MCL1

Targeting p97/Valosin-Containing Protein Promotes Hepatic Stellate Cell Senescence and Mitigates Liver Fibrosis. (PubMed, DNA Cell Biol) - "In addition, in vivo experiments confirmed that CB-5083 facilitated HSC senescence and reduced YAP expression. These findings underscore the potential of pharmacological targeting p97/VCP to induce HSC senescence and alleviate liver fibrosis."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Targeted Protein Degradation • CDKN1A • GPX4

Proteomics analysis reveals the differential impact of the p97 inhibitor CB-5083 on protein levels in various cellular compartments of the HL-60 cell line. (PubMed, MicroPubl Biol) - "Here, we examined the impact of CB-5083 treatment in another cancer model, the HL-60 acute myeloid leukemia cell line, employing subcellular fractionation combined with label-free proteomics to analyze changes in protein levels across cytoplasmic, nuclear, and insoluble membrane protein compartments. The results reveal distinct compartment-specific protein regulation, providing insight into p97/VCP's cellular mechanisms and its potential for targeted therapeutic applications."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation

EMC3 regulates trafficking and pulmonary toxicity of the SFTPCI73T mutation associated with interstitial lung disease. (PubMed, J Clin Invest) - "Treatment of SftpcI73T knock-in mice and SFTPCI73T expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the specific VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing novel therapeutical targets for SFTPCI73T-associated interstitial lung disease."

Journal • Interstitial Lung Disease • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • SFTPC

Molecular Signatures of CB-6644 Inhibition of the RUVBL1/2 Complex in Multiple Myeloma. (PubMed, Int J Mol Sci) - "Footprinting analysis identified transcription factors implied in modulating chromatin accessibility in response to CB-6644 treatment, including ATF4/CEBP and IRF4. Lastly, integrative analysis of transcription responses to various chemical compounds of the molecular signature genes from public gene expression data identified CB-5083, a p97 inhibitor, as a synergistic candidate with CB-6644 in MM cells, but experimental validation refuted this hypothesis."

Journal • Burkitt Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • ATF4 • CEBPA • IRF4 • MBD4 • MED1 • RUVBL1

Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors. (PubMed, Commun Chem) - "Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models...A key structural moiety of the inhibitor affects the rotameric conformations of interacting side chains, indirectly modulating the N-terminal domain conformation in p97 R155H mutant. The differential effects of inhibitor binding to wild-type and mutant p97 provide insights into drug design with enhanced specificity, particularly for oncology applications."

Journal • Infectious Disease • Oncology

Exploring in vivo combinatorial chemo-immunotherapy: Addressing p97 suppression and immune reinvigoration in pancreatic cancer with tumor microenvironment-responsive nanoformulation. (PubMed, Biomed Pharmacother) - "In this innovative preclinical investigation, the VCP/p97 inhibitor CB-5083 (CB), miR-142, a PD-L1 inhibitor, and immunoadjuvant resiquimod (R848; R) were synergistically encapsulated in solid lipid nanoparticles (SLNs)...This versatile nanoformulation allows tailored adjustment of the tumor microenvironment, thereby optimizing the localized delivery of combined therapy. These compelling findings advocate the potential development of a pH-sensitive, three-in-one PGA-PEG nanoformulation that combines a VCP inhibitor, a PD-L1 inhibitor, and an immunoadjuvant for cancer treatment via combinatorial chemo-immunotherapy."

Journal • Preclinical • Tumor microenvironment • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ATF6 • CSF2 • EGFR • IFNG • IL4 • MIR142 • TGFB1 • TNFA

ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons. (PubMed, Stem Cell Reports) - "Finally, inhibition of the ATPase activity of p97 using the inhibitor CB-5083 rescues lysophagy defects in mutant motor neurons. These results add to the evidence that endo-lysosomal dysfunction is a key aspect of disease pathogenesis in p97-related disorders."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Proteinopathy

An innovative nanoformulation utilizing tumor microenvironment-responsive PEG-polyglutamic coating and dynamic charge adjustment for specific targeting of ER stress inducer, MicroRNA, and immunoadjuvant in pancreatic cancer: In vitro investigations. (PubMed, Int J Biol Macromol) - "CB-5083, a novel valosin-containing protein (VCP)/p97 inhibitor that disrupts proteasomal degradation and induces endoplasmic reticulum stress (ERS) accumulation, was evaluated as an inducer of immunogenic cell death (ICD) in PDAC treatment...Combined treatment blocked VCP, arrested the cell cycle, inhibited EMT, triggered ERS-mediated autophagy/apoptosis, and stimulated robust ICD via the release of damage-associated molecular patterns. This adaptable nanoformulation, displaying pH-sensitive PEG-PGA de-coating and precisely targeting EGFR, PD-L1, and ER, serves to hinder EMT and immune evasion, subsequently amplifying ICD in PDAC cells and the TME."

Journal • Preclinical • Tumor microenvironment • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ATF6 • EGFR • IFNG • IL10 • IL6 • MIR142 • MRC1 • TGFB1 • TNFA