NMS-873 / Nerviano Medical Sciences - LARVOL DELTA

Valosin-Containing Protein (VCP/p97) Mediates Neuroendocrine Differentiation in Prostate Cancer Cells Through Pim1 Signaling Inducing Autophagy. (PubMed, Prostate) - "VCP drives NED in PCa cells through a complex interplay involving the Pim1 axis and autophagy pathways. These findings highlight the potential of targeting VCP/p97 and its associated mechanisms as therapeutic strategies to inhibit NED progression."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • IL6 • MYC • PIM1 • SQSTM1 • STK11 • VCP

VCP regulates early tau seed amplification via specific cofactors. (PubMed, Mol Neurodegener) - "Divergent effects on tau seeding of chemical inhibitors and cofactor reduction indicate that VCP regulates this process. This is consistent with a cytoplasmic processing complex centered on VCP that directs seeds acutely towards degradation vs. amplification."

Journal • CNS Disorders • Proteinopathy • ATXN3 • UBE4B

Ergosterol Peroxide affects the VCP/ANKZF1 complex spatial relationship and interaction in IBC cells (SABCS 2024) - "Veh, EP, and NMS 873 (VCP inhibitor, positive control) were administered, to detect changes in PLA signals for VCP and ANKZF1...In general, EP affects VCP/ANKZF1 spatial relationship and interaction in IBC cells. Further research is needed to comprehensively understand the intricate mechanisms through which EP exerts its antineoplastic effects in IBC cells."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Inflammatory Breast Cancer • Triple Negative Breast Cancer • ANKZF1 • ER • HER-2 • PGR

p97 inhibits integrated stress response-induced neuronal apoptosis after subarachnoid hemorrhage in mice by enhancing proteasome function. (PubMed, Exp Neurol) - "However, the detrimental effects of NMS-873 and PS-341 in mice with SAH were mitigated by the administration of the ISR inhibitor ISRIB. These results suggest that p97 can promote neuronal survival and improve neurological function in mice after SAH. The anti-neuronal apoptosis effect of p97 is achieved by enhancing proteasome function and inhibiting the overactivation of the ISR apoptotic pathway."

Journal • Preclinical • CNS Disorders • Hematological Disorders • Subarachnoid Hemorrhage • Vascular Neurology

Double-targeting of pancreatic ductal adenocarcinoma (PDAC): Unveiling the potent combination of NMS-873 and BAY-876 (AACR 2024) - "This study underscores the remarkable synergy observed in mouse PDAC cell lines with a particular emphasis on the heightened efficacy against cell populations that are more resistant to NMS-873. These results warrant further investigation to elucidate the underlying molecular mechanisms and validate these findings in clinical settings."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • SLC2A1

Allosteric inhibitors of VCP/ p97 as a therapeutic approach to cancer (ACS-Sp 2024) - "The triazole series was based on literature reports of a scaffold represented by NMS-873...An extensive medicinal chemistry optimization effort to improve those properties employed multiple bioisosteric replacements, strategic incorporation of fluorine and the identification of the eutomer and distomer. The resultant compounds exhibited effects on biomarkers that reflect p97 inhibition and in vivo efficacy in cancer xenograft models."

CNS Disorders • Infectious Disease • Oncology • Targeted Protein Degradation

APP AND TAU PROTEINS ARE DIFFERENTIALLY REGULATED BY VCP INTERACTORS (ADPD 2024) - " To further decipher the potential mechanism, VCP interactome was achieved by mass spectrometry following immunoisolation from cells treated or not with NMS-873, the most potent and specific VCP pharmacological inhibitor... Our results suggest that VCP contributes to regulate Tau phosphorylation and APP metabolism, which could represent an attractive therapeutic target for AD."

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Myositis • Rare Diseases • MAPT • VCP

Rational Drug Design of VCP Inhibitors to Enhance NIS Function in Radioiodide Therapy (ATA 2023) - " Based on 3D modelling and iterative drug construction, we designed 21 novel analogues based on clotrimazole and the allosteric VCPi UPDC30425, all with improved predicted bioavailability (LogP), and synthesised 4 de novo compounds based on CryoEM high-resolution features of VCPi NMS873 docking to VCP. Our study demonstrates a promising drug strategy utilising a disulfiram metabolite to enhance NIS function in vivo, with clinical potential to improve treatment in RAI-refractory thyroid cancer."

Endocrine Cancer • Metabolic Disorders • Oncology • Solid Tumor • Thyroid Gland Carcinoma

Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer. (PubMed, ACS Med Chem Lett) - "Starting from a known allosteric inhibitor, NMS-873, we systematically optimized this scaffold, in particular, by applying a benzene-to-acetylene isosteric replacement strategy, specific incorporation of F, and eutomer/distomer identification, which led to compounds that exhibited nanomolar biochemical and cell-based potency. In cellular pharmacodynamic assays, robust effects on biomarkers of p97 inhibition and apoptosis, including increased levels of ubiquitinated proteins, CHOP and cleaved caspase 3, were observed. Compound (R)-29 (UPCDC-30766) represents the most potent allosteric inhibitor of p97 reported to date."

Journal • Oncology • Targeted Protein Degradation • CASP3

Targeting endoplasmic reticulum associated degradation pathway combined with radiotherapy enhances the immunogenicity of esophageal cancer cells. (PubMed, Cancer Biol Ther) - "We aimed to investigate the efficacy of endoplasmic reticulum (ER)-associated protein degradation (ERAD) inhibitors (EerI and NMS-873) in enhancing radiation-induced ICD in esophageal cancer (EC)...ICD hallmark genes, especially CALR, are correlated to immune cell infiltration and clinical outcomes in EC. The present results demonstrated an important method to improve the immunogenicity of EC cells for enhanced antitumor immune response."

Journal • Esophageal Cancer • Gastrointestinal Cancer • Oncology • Targeted Protein Degradation • CALR • HMGB1

Yeast Smy2 and its human homologs GIGYF1 and -2 regulate Cdc48/VCP function during transcription stress. (PubMed, Cell Rep) - "Similarly, the Smy2 homologs GIGYF1 and -2 affect the transcription stress response in human cells and regulate the function of the Cdc48 homolog VCP/p97, presently being explored as a target for cancer therapy. Indeed, we show that the apoptosis-inducing effect of VCP inhibitors NMS-873 and CB-5083 is GIGYF1/2 dependent."

Journal • Oncology

P97/VCP ATPase inhibitors can rescue p97 mutation-linked motor neuron degeneration. (PubMed, Brain Commun) - "We also find that two p97 inhibitors, CB-5083 and NMS-873, restore some dysregulated protein levels. In addition, two p97 inhibitors and a food and drug administration-approved cyclin-dependent kinase 4/6 inhibitor, Abemaciclib, can rescue motor neuron death. Overall, we successfully used iPSC-derived motor neurons, identified dysregulated proteome and transcriptome and showed that p97 inhibitors rescue phenotypes in this disease model."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology • Myositis • Orthopedics

NMS-873 Leads to Dysfunctional Glycometabolism in A p97-Independent Manner in HCT116 Colon Cancer Cells. (PubMed, Pharmaceutics) - "Adenosine triphosphate (ATP)-competitive p97 inhibitor CB-5339, the successor of CB-5083, is being evaluated in Phase 1 clinical trials for anti-cancer therapy. We then used proteome integral solubility alteration with a temperature-based method (PISA T) to identify NDUFAF5 as one of the potential targets of NMS-873 in the mitochondrial complex I. We also demonstrated that glycolysis inhibitor 2-DG enhanced the anti-proliferative effect of NMS-873. The polypharmacology of NMS-873 can be advantageous for anti-cancer therapy for colon cancer."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Cryo-EM structure of dodecamer human p97 in complex with NMS-873 reveals S-G peptide plays critical role for D2 ring oligomerization. (PubMed, Biochem Biophys Res Commun) - "Here we report the Cryo-EM structure of full-length human p97 dodecamer in 3.0 Å resolution, the structure was captured in ADP-bound form but only D1 ATPase sites were well occupied by nucleotide and D2 sites are empty, furthermore, 12 non-ATP-competitive inhibitors of NMS-873 bound in the interface between each p97 monomer. We also found that the C-terminal S-G (765-'SRGFGSFRFPSGNQG'-779) peptide plays critical roles for the D2 ring oligomerization, biochemical and electron microscopy studies confirm that the S-G peptide could induce the D2 ring itself to form the heptamer, this give new insights how p97 protomers assemble to the biological functional multimers."

Journal

Temporal proteomics reveal specific cell cycle oncoprotein downregulation by p97/VCP inhibition. (PubMed, Cell Chem Biol) - "Western blot analysis validated the degradation of cyclin D1 and Securin, which depends on proteasome but not on p97. Differing regulation of cell cycle proteins by p97 and the proteasome may, therefore, explain the therapeutic efficacy of p97 inhibitors in colon cancer."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Immunology • Oncology • Solid Tumor • CCND1

Phospho-Ser-VCP Drives Resistance of Pancreatic Ductal Adenocarcinoma to Genotoxic Chemotherapies and Predicts the Chemo-Sensitizing Effect of VCP Inhibitor. (PubMed, Cancers (Basel)) - "Importantly, DNA damage-induced pSer-VCP rather than total VCP levels in PDAC cell lines predict their chemotherapy response and chemo-sensitizing ability of selective VCP inhibitor NMS-873. Therefore, pSer-VCP drives genotoxic chemotherapy resistance of PDAC, and can potentially be used as a predictive biomarker as well as a sensitizing target to enhance the chemotherapy response of PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Mechanistic insight into substrate processing and allosteric inhibition of human p97. (PubMed, Nat Struct Mol Biol) - "In addition, we determined the cryo-EM structure of human p97 in complex with NMS-873, a potent p97 inhibitor, at a resolution of 2.4 Å. The structures showed that NMS-873 binds at a cryptic groove in the D2 domain and interacts with the ISS motif, preventing its conformational change and thus blocking substrate translocation allosterically."

Journal • Cardiovascular • Targeted Protein Degradation

NMS-873 functions as a dual inhibitor of mitochondrial oxidative phosphorylation. (PubMed, Biochimie) - "Our further investigation uncovered an unexpected off-target effect of NMS-873 on mitochondrial oxidative phosphorylation, specifically as a dual inhibitor of Complex I and ATP synthase. This work points to the need for caution regarding the interpretation of cell survival data associated with NMS-873 treatment and indicates that cellular toxicity associated with its use may be caused by both VCP/p97-dependent and VCP/p97-independent mechanisms."

Journal

A covalent p97/VCP ATPase inhibitor can overcome resistance to CB-5083 and NMS-873 in colorectal cancer cells. (PubMed, Eur J Med Chem) - "Proteomic analysis of PPA-treated HCT116 revealed Gene Ontology enrichment of known p97 functional pathways such as the protein ubiquitination and the ER to Golgi transport vesicle membrane. In conclusion, we have identified and characterized PPA as a selective covalent p97 inhibitor, which will allow future exploration to improve the potency of p97 inhibitors with different mechanisms of action."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Infectious Disease • Oncology • Solid Tumor • Targeted Protein Degradation

Valosin-containing protein ATPase activity regulates the morphogenesis of Zika virus replication organelles and virus-induced cell death. (PubMed, Cell Microbiol) - "Moreover, short treatment with the VCP inhibitors NMS-873 or CB-5083 drastically decreased the abundance and size of ZIKV-induced convoluted membranes. Altogether, this study identifies VCP as a host factor required for ZIKV life cycle and more precisely, for the maintenance of viral replication factories. Our data further support a model in which convoluted membranes regulate ZIKV life cycle by impacting on mitochondrial functions and ZIKV-induced death signals in order to create a cytoplasmic environment favourable to viral replication."

Journal • Dengue Fever • Infectious Disease

Anti-HCMV activity by an irreversible p97 inhibitor LC-1310. (PubMed, Med Chem Res) - "We tested irreversible p97-targeting compounds for their ability to inhibit the replication of multiple viruses compared to the known p97 inhibitors NMS-873 and CB-5083. Our results indicate that overall cellular toxicity for p97 compounds provides a challenge for antivirals targeting p97. However, we identified one compound with sub-micromolar activity against human cytomegalovirus and improved cell viability to provide evidence for the potential of irreversible p97 inhibitors as antivirals."

Journal • Cytomegalovirus Infection

Spironolactone-induced XPB degradation requires TFIIH integrity and ubiquitin-selective segregase VCP/p97. (PubMed, Cell Cycle) - "We show that spironolactone induces a dose- and time-dependent degradation of XPB but not XPD, and that the XPB degradation is blocked by VCP/p97 inhibitors DBeQ, NMS-873, and neddylation inhibitor MLN4924...Also, VCP/p97 interacts with XPB upon treatment of spironolactone and proteasome inhibitor MG132, while the VCP/p97 adaptor UBXD7 binds XPB and its ubiquitin conjugates...These results indicate that the spironolactone-induced XPB proteolysis requires VCP/p97 function and that XPB within holo-TFIIH rather than core-TFIIH is more vulnerable to spironolactone-induced proteolysis. Abbreviations NER: nucleotide excision repair; TFIIH: transcription factor II H; CAK: Cdk-activating kinase (CAK) complex; XPB: Xeroderma Pigmentosum type B; VCP/p97: valosin-containing protein/p97; Cdk7: cyclin-dependent kinase 7; NAE: NEDD8-activating enzyme; IP: immunoprecipitation."

Journal • Oncology • Targeted Protein Degradation • CDK7

Targeting VCP to enhance pancreatic cancer response to DNA damaging agents (AACR 2018) - "To investigate the mechanism by which VCP modulates response to cisplatin-induced DNA damage, the effect of VCP functionality loss in decreasing cell viability was validated using two pharmacological VCP inhibitors, NMS-873 and CB-5083, in a panel of pancreatic cancer cell lines. Our findings suggest VCP could be a potential therapeutic target for pancreatic and other cancers. Confirming how VCP regulates DSB repair will allow development of novel strategies to enhance the efficacy of DNA damaging agents in cancer."

Ovarian Cancer • Pancreatic Cancer

Targeting DNA repair with the combination of p97 and HDAC6 inhibitors in mantle cell lymphoma (AACR 2018) - "We report that treatment of MCL cells with the p97 inhibitors, DBeQ, ML240, NMS-873 and CB-5083 induces ER stress markers GRP78 and CHOP and resulted in dose-dependent apoptosis. Finally, treatment of MCL cells with p97 inhibitors and ACY-1215 results in synergistic apoptotic cell death in MCL cells. Collectively our studies create a strong rationale to test efficacy of the combination of p97 inhibitors in combination with HDAC6 inhibitors in MCL."

BRCA Biomarker • Mantle Cell Lymphoma

Identification of novel sodium iodide symporter (NIS) interactors which modulate iodide uptake (AACR 2018) - "...Pharmacological inhibitor studies identified that the VCP inhibitors Eeyarastatin-1 and NMS-873 overcome VCP inhibition of NIS function...Our data suggest a possible model for NIS trafficking: NIS dimerises in the ER, a process monitored by VCP and the ERAD pathway, with correctly processed and folded NIS being trafficked to the PM via C-terminal interaction with Arf4. We thus now identify two new potential therapeutic targets for enhancing radioiodide uptake in patients with radioiodide-refractory thyroid cancer."

IO Biomarker • Breast Cancer • Head and Neck Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Thyroid Cancer