daporinad (APO866) / Valerio Therap - LARVOL DELTA

Artificial Intelligence-Guided Prioritization and Experimental Evaluation of Synergistic Target Combinations for Breast Cancer Therapy. (PubMed, Pharmaceuticals (Basel)) - "The corresponding inhibitors, LQZ-7I, FK866, and topotecan, exhibited synergistic antiproliferative activity at multiple molar ratios, with combination index values below 1. The BIRC5-NAMPT-TOP1 combination showed reproducible phenotypic activity in the tested genetic and pharmacological models. These findings support the use of DeepMDS as a hypothesis-generation tool for higher-order target prioritization."

Journal • Breast Cancer • Hematological Disorders • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BIRC5 • ER • NAMPT • TOP1

Beyond NAD Depletion: SARM1-Induced ATP Collapse Involves Direct ATP Degradation and Mitochondrial Dysfunction and Is Pharmacologically Reversible. (PubMed, Biology (Basel)) - "VER preserved NAD and ATP during SARM1 activation but failed to rescue FK866-mediated NAD starvation, thereby distinguishing CZ-48/SARM1-driven cytotoxicity from generic NAD depletion...ATPase-related perturbations, including thapsigargin and bafilomycin A1, also protected cells from CZ-48-induced death, further supporting a central role for ATP collapse in sarmoptosis. iTRAQ proteomics, MitoSOX Red staining, and DiOC6(3) staining revealed that CZ-48 treatment was associated with mitochondrial and metabolic remodeling, mitochondrial ROS accumulation, and mitochondrial depolarization, all of which were mitigated by VER. Collectively, these findings support a convergent ATP-collapse model in which SARM1 activation promotes NAD depletion, directly consumes ATP, and is associated with mitochondrial dysfunction that may amplify ATP-production failure."

Journal • Metabolic Disorders • CDC37 • HSP90AA1

NAMPT activation protects against myocardial ischemia/reperfusion injury via FSP1-CoQ10 ferroptosis defense. (PubMed, Life Sci) - "NAMPT activation attenuates MIRI by restoring redox homeostasis and sustaining FSP1/CoQ10-mediated ferroptosis defense, likely through NAD(P)H-dependent metabolic coupling. These findings identify the NAMPT-FSP1/CoQ10 axis as a potential metabolic target for myocardial protection against reperfusion injury."

Journal • Cardiovascular • Hematological Disorders • Metabolic Disorders • Myocardial Infarction • Myocardial Ischemia • Reperfusion Injury • AIFM2 • NAMPT

scRNA-seq and bulk RNA-seq reveal the characteristics of macrophage copper metabolism and establish a risk signature in hepatocellular carcinoma. (PubMed, Transl Cancer Res) - "Drug sensitivity analysis nominated Daporinad as a computationally predicted candidate compound, supporting Daporinad as a pharmacogenomic candidate for follow-up investigation. By integrating scRNA-seq and bulk RNA sequencing (RNA-seq) data, we constructed a macrophage copper metabolism-associated prognostic signature for HCC. The risk score was associated with survival, immune microenvironment features and predicted drug response, providing a transcriptomic framework for risk stratification and therapeutic hypothesis generation."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • SPP1

Aerobic exercise combined with FK866 ameliorates Alzheimer's disease-like pathology in APP/PS1 mice with NAMPT abnormality. (PubMed, Front Immunol) - "Compared with exercise alone, the combined intervention with exercise and FK866 further improved selected indices related to Aβ pathology, neuroinflammation, oxidative stress, and mitochondrial damage. These additional effects may be associated with increased NAD+ biosynthesis through the NMNAT3 pathway, as well as reduced NAD+ consumption and neuroinflammatory activation through the suppression of CD38 and PARP1 expression."

IO biomarker • Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • Metabolic Disorders • NAMPT • PARP1

Daporinad Potently Induces Cell Death in Ph+ Acute Lymphoblastic Leukemia SUP-B15 Cells Independent of the Intrinsic Apoptotic Pathway (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi) - "APO866 could potently induce SUP-B15 cell death by depleting intracellular NAD+ levels, a process that lacks canonical features of the intrinsic apoptotic pathway. Moreover, its cytotoxicity persists even with deficiencies in key regulators of this pathway, indicating a mechanism of action that is independent of intrinsic apoptosis."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • CASP3 • NAMPT • TP53

Targeting the NAD+ salvage pathway blocks metabolic recovery and enhances β-lapachone toxicity in NQO1-expressing glioblastoma cells. (PubMed, Cancer Res Commun) - "We demonstrate that targeting this pathway with the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866 prevents NAD+ regeneration after β-lap exposure and enhances β-lap cytotoxicity in NQO1-expressing GBM. Altered NAD+ metabolism in GBM represents a potential metabolic vulnerability. Our results suggest targeting NQO1-expressing GBM with NQO1 bioactivatable compounds in combination with NAMPT-inhibitors, is a promising therapeutic strategy for the treatment of GBM."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • NAMPT • NQO1

Integrative multi-omics analysis identifies histone methyltransferase SUV420H2 as a prognostic biomarker in clear cell renal cell carcinoma. (PubMed, Discov Oncol) - "Drug-sensitivity profiling further showed that high SUV420H2/RNA-processing signature expression conferred increased sensitivity to FK866 (NAMPT inhibitor), topoisomerase inhibitors, and apoptosis-inducing agents, identifying potential therapeutic associations that warrant further investigation. Collectively, our findings suggest that SUV420H2 is a multi-layer dysregulated epigenetic regulator associated with ccRCC progression and highlight its RNA-processing network as a promising prognostic and therapeutic axis."

Biomarker • Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD4 • CD8 • CLK2 • KMT5C • NAMPT • SNRNP70

Ergothioneine attenuates age-related declines in circadian rhythmicity. (PubMed, Biochem Biophys Res Commun) - "Aging-associated NAD+ decline was modeled using FK866, a NAMPT inhibitor that depletes intracellular NAD+, which reduced rhythm amplitude, lengthened the period, and increased cycle-to-cycle variability. EGT may ameliorate age-related circadian decline by improving intracellular redox balance and NAD+ metabolism. Given that EGT crosses the blood-brain barrier, it may represent a novel nutritional strategy to preserve circadian function during aging."

Journal • NAMPT • PER2

Multi-omics analysis positions DNA2 at the interface of genome integrity programs and tumor behavior in pan-cancer. (PubMed, Funct Integr Genomics) - "According to the pharmacogenomic analysis from GDSC2 dataset, tumor cells that express higher DNA2 are more sensitive to Tozasertib, and Daporinad. DNA2 is at the core of several interrelated modules, including flap processing, telomerase extension, and cell-cycle progression, according to the enrichment study. These findings have suggested DNA2 as a therapeutic vulnerability in cancer, a context-dependent biomarker with implications for treatment response, prognosis, and immunity."

Journal • Pan tumor • Adrenal Cortex Carcinoma • Endometrial Cancer • Genito-urinary Cancer • Mesothelioma • Oncology • Solid Tumor • DNA2

The nicotinamide phosphoribosyltransferase inhibitor FK866 restricts influenza A virus replication by perturbing viral polymerase activity. (PubMed, J Virol) - "FK866 could interfere with the viral polymerase activity, thereby limiting the synthesis of IAV viral RNA, complementary RNA, and messenger RNA. These findings reveal that the NAMPT inhibitor FK866 restricts IAV replication by perturbing viral polymerase activity and provide insights into the development of potential antivirals against IAV infection."

Journal • Infectious Disease • Influenza • Respiratory Diseases • NAMPT

NAMPT activity plays a key role in driving autoimmune processes that mediate beta-cell death and type 1 diabetes development in mice. (PubMed, Cell Death Dis) - "MLDS mice were administered the NAMPT inhibitor FK866 (10 mg/kg; IP) or saline equivalent for 16 days...NAMPT inhibition may be able to prevent beta-cell death and thus represent a novel therapeutic approach for T1D. The effects of increased NAD levels on islet inflammation require in-depth characterisation and caution should be exercised with regard to the use of NAD boosting supplements, particularly in individuals at risk of developing T1D."

Journal • Preclinical • Diabetes • Immunology • Inflammation • Metabolic Disorders • Type 1 Diabetes Mellitus • CD4 • CD8 • IFNG • IL1B • NAMPT • TNFA

Hydrogen Sulfide Protects Against Cerebral Ischemia-Reperfusion Injury in Rats via S-Sulfhydrating NAMPT to Enhance Mitochondrial Function and Autophagy in Cerebrovascular Endothelial Cells. (PubMed, Pharmaceuticals (Basel)) - "The contributions of NAMPT and S-sulfhydration were validated using FK866 and dithiothreitol (DTT), respectively...LC-MS/MS analysis confirmed enhanced S-sulfhydration at Cys39 and Cys397 residues of NAMPT following H2S exposure. H2S exerts neuroprotection against cerebral I/R injury in rats through S-sulfhydration-mediated activation of NAMPT, which improves mitochondrial performance and stimulates autophagy in cerebrovascular ECs."

Journal • Preclinical • Cardiovascular • CNS Disorders • Ischemic stroke • Reperfusion Injury • Vascular Neurology • NAMPT

Intracellular NAD+ Depletion Increases Prostanoid Production via p38/COX2 Signalling in FK866-Induced Senescent Human Umbilical Vein Endothelial Cells. (PubMed, J Cell Mol Med) - "Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD+, following FK866 treatment restored intracellular NAD+ levels, reduced the cellular senescence-like phenotype and attenuated the production of PGF1α and TXB2. These results suggest that intracellular NAD+ appears to regulate prostanoid production in HUVECs under conditions of acute depletion."

Journal • Cardiovascular • MT-CO2 • NAMPT

Combination of NAMPT inhibitors plus pyrimidine analog antimetabolites floxuridine and 5-FU impair rhabdomyosarcoma proliferation and survival (AACR 2026) - "Previously, we showed that RMS is highly sensitive to NAMPT inhibition, with in vivo RMS models undergoing tumor regression upon treatment with the NAMPT inhibitor OT-82...To identify synergistic drug combinations, we used a matrix drug screen of 2 RMS cell lines (Rh30 (fusion-positive (FP)) and Rh36 (fusion-negative (FN)) testing 2 NAMPT inhibitors (daporinad and GNE-618) in combination with 62 other anticancer agents...To evaluate this combination for potential translation into the clinic, we extended our testing to include clinical agents, including RPT1G (Remedy Plan Therapeutics), a NAMPT inhibitor currently under early phase evaluation, and 5-FU, a prodrug of floxuridine...Efficacy experiments are ongoing and will be reported. These findings demonstrate that combining NAMPT inhibitors with floxuridine or 5-FU results in significant synergy and preliminarily suggest that this is a promising and feasible combination regimen for patients with RMS."

Oncology • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • NAMPT • TYMS

Inhibiting Nampt signaling promotes M2 macrophage polarization to enhance bone regeneration in periodontitis. (PubMed, Front Bioeng Biotechnol) - "Murine macrophages (RAW264.7) were treated with the NAMPT inhibitor FK866 or the enzymatic product of NAMPT and NAD+ precursor nicotinamide mononucleotide to assess polarization status and were co-cultured with MC3T3-E1 osteoblasts to evaluate osteogenic potential...Inhibition of the NAMPT signaling pathway induces M2 macrophage polarization, alleviating inflammation and facilitating osteogenesis within periodontal bone defects. These findings identify NAMPT as a promising therapeutic target for modulating the host response and promoting bone regeneration in periodontitis."

Journal • Dental Disorders • Inflammation • Osteoporosis • Periodontitis • NAMPT • TRAP

Increasing the therapeutic vulnerability of heterogenous cell phenotypes within prostate cancer (AACR 2024) - "Tested compounds with differential sensitivity between aggressive and non-aggressive cells were those inhibiting histone deacetylase (vorinostat, fimepinostat, and pracinostat), proteasomes (bortezomib, delanzomib, ixazomib), topoisomerases (gimatecan and daunorubicin), and other compounds identified independently by us targeting nicotinamide phosphoribosyl transferase (FK866) and DNA (bleomycin). Funding was provided by the University of Arizona Cancer Center (NCI-P30 CA23074 and NCI-R01 CA159406) and by the Partnership in Native American Cancer Prevention at the University of Arizona (U54CA143924) and Northern Arizona University (U54CA143925). Collaborators at NCATS were supported by the intramural research program."

Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • CDH1 • CLDN4 • CLDN7 • KRT6A • ZEB1

NAMPT-enriched small extracellular vesicle promotes liver cancer via activation of SLC27A4-mediated glycolysis (AACR 2024) - "NAMPT is enriched in metastatic HCC sEV. sEV-NAMPT regulates the promoting effect of HCC-sEV in glycolysis and oncogenesis. SLC27A4 function as the downstream target that promotes HCC progression via glycolysis."

IO biomarker • Gastrointestinal Cancer • Liver Cancer • Oncology • Solid Tumor • NAMPT • TLR4

NAMPT inhibitor-resistant rhabdomyosarcoma models exhibit alterations in metabolic and genomic profiles [WITHDRAWN] (AACR 2025) - "Treatment with the clinical NAMPT inhibitor OT-82 results in complete tumor regressions in vivo, however, upon intermittent treatment, acquired resistance develops in some in vivo models...Resistance to multiple other NAMPT inhibitors (daporinad and KPT-9274) was observed in one of the resistant cell lines...Whole exome sequencing revealed that each resistant cell line has a distinct, previously unreported mutation in NAMPT. Together, these data suggest that acquired resistance to NAMPT inhibitors in RMS models involves cellular alterations in the biochemical, metabolomic, and genomic profiles of cells."

Oncology • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • NAMPT • QPRT

Host Cell Central Carbon Metabolism and Cellular NAD+ Pool Regulate Efficient Replication of Vesicular Stomatitis Virus. (PubMed, Viruses) - "Restoration of viral replication by NAD+ precursors in the presence of 6-AN or suppression of replication by the NAMPT inhibitor FK866 suggested NAD+ availability as a critical determinant of VSV replication...Collectively, these findings demonstrate that VSV replication is tightly coupled to metabolic programs, particularly those governing energy production and NAD(P)H balance. This work provides a metabolic framework for optimizing oncolytic VSV therapies and suggests that metabolic interventions in cancer treatment may influence oncolytic virus efficacy."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • NAMPT

The NAMPT Inhibitor FK866 Attenuates DEN-Induced Liver Fibrosis in Mice. (PubMed, Biol Pharm Bull) - "Further studies revealed that this therapeutic effect was achieved by inhibiting the NAD+ level, as well as the protein expression of NAMPT, PARP1, and inflammatory factors, including interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α, and P65. In conclusion, FK866 exhibits therapeutic potential for the treatment of liver fibrosis."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Oncology • FN1 • IL1B • IL6 • NAMPT • TNFA

Nicotinamide N-Methyl Transferase (NNMT) Sustains Innate Sensitivity to NAMPT Inhibition in YAP-dependent Stem-like/Mesenchymal Prostate Cancer. (PubMed, Int J Biol Sci) - "Resistance to NAMPT inhibitors, such as FK866, remains a key limitation to their clinical translation...These findings support the use of NNMT as a predictive biomarker for NAD+-targeting therapies and provide mechanistic insight into a metabolic vulnerability of the CRPC-SCL subtype. Targeting the YAP/NNMT/NAMPT axis may represent a novel strategy for treating stem-like/mesenchymal, therapy-resistant prostate cancers."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • NAMPT • NNMT

Targeting Metabolic and pH Regulatory Pathways in Cancer via Dual Inhibition of Nicotinamide Phosphoribosyltransferase and Carbonic Anhydrases IX and XII. (PubMed, J Med Chem) - "In three-dimensional (3D) spheroids, compound 45 reduced the cumulative spheroid area approximately 10-fold more than the single-target inhibitors FK866 or SLC-0111 and induced apoptosis through NAD depletion, mitochondrial dysfunction, and suppression of ERK/mTOR signaling. These results support dual hCA IX/XII-NAMPT inhibition as an effective strategy to impair tumor growth and survival under hypoxic stress."

Journal • Brain Cancer • Colorectal Cancer • Glioblastoma • Kidney Cancer • Metabolic Disorders • Oncology • Renal Cell Carcinoma • Solid Tumor • NAMPT

Single-Cell RNA sequencing identifies NAMPT as a potential therapeutic target in autoimmune uveitis. (PubMed, J Adv Res) - "Inhibiting NAMPT can reverse the imbalance of effector T (Teff)/Treg cells by suppressing the expression of Hif1α in CD4+T cells, thereby effectively alleviating the symptoms of EAU. Therefore, NAMPT might be a potential target for AU."

Journal • Immunology • Ocular Inflammation • Ophthalmology • Uveitis • CD4 • HIF1A • NAMPT

Exploring the role of CCT7 in prognosis, cell cycle regulation, and immune microenvironment remodeling of lung adenocarcinoma based on multi-omics datasets and functional experiments. (PubMed, Biochim Biophys Acta Gen Subj) - "CCT7 acts as an independent prognostic biomarker in LUAD, driving progression through cell cycle regulation, microenvironment remodeling, and immune modulation. It holds promise as a therapeutic target and guide for personalized LUAD treatment."

Journal • Tumor mutational burden • Immune Modulation • Immunology • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • FOXM1 • MIR145 • TMB