OT-82 / OncoTartis - LARVOL DELTA

Discovery of a Potent NAMPT-Targeting PROTAC for the Suppression of Triple-Negative Breast Cancer via Macrophage Reprogramming. (PubMed, J Med Chem) - "Herein, we designed and synthesized a series of NAMPT-targeting proteolysis-targeting chimeras (PROTACs) using OT-82 as the warhead...In orthotopic TNBC allograft models, A13 achieved significant tumor growth inhibition (TGI = 82.7%) without obvious toxicity and effectively suppressed lung metastasis. These results demonstrate that NAMPT degradation suppresses primary tumor growth and lung metastasis in TNBC, offering a promising lead compound and therapeutic strategy."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • NAMPT

Blockade of the NAD+ salvage pathway synergizes with irinotecan in chemo-resistant microsatellite stable colorectal cancer models (EACR 2026) - "Thus, the identification of novel regimens effective in MSS mCRC primary or secondary refractory to chemotherapy is a major unmet clinical need.Material and We identified a subset of MSS POLE wild-type RAS/BRAF mutant CRC cell lines resistant to the standard of care chemotherapeutic agents irinotecan, oxaliplatin, and 5-fluorouracil either alone or in combination recapitulating FOLFOX and FOLFIRI regimens... Combinatorial treatment with NAMPT inhibitors and irinotecan is synergic in chemorefractory MSS CRC preclinical models by concomitantly impairing DNA repair and mitochondrial function. These findings provide the biological rationale for a proof-of-concept trial in chemo-refractory MSS mCRC patients."

Preclinical • Colorectal Cancer • Oncology • Solid Tumor • BRAF • NAMPT • PARP1

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) impairs cellular viability, affects energy metabolism, induces DNA damage, and drives tumor regression in preclinical models of neuroblastoma (AACR 2026) - "We used 2 clinical NAMPTis under early phase study (OT-82 and KPT-9274) to validate our drug screen results in 10 molecularly diverse NB cell lines including 2 NB PDX-derived cell lines. Across models, 23/26 mouse tumors had average volume reductions of 67% (range 10%-99%). Together, these data demonstrate that in NB, multiple critical pathways are impacted by the loss of NAD+ mediated by NAMPT inhibition and suggest NAMPTis may have translational potential as a novel agent against NB."

Preclinical • Neuroblastoma • Oncology • Solid Tumor • 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

Nicotinamide phosphoribosyltransferase (NAMPT) inhibitor-resistant rhabdomyosarcoma (RMS) models exhibit alterations in metabolic and genomic profiles (AACR 2026) - "These findings are consistent with functional studies demonstrating that Rh30-mRes is resistant to multiple other NAMPT inhibitors whereas RD-mRes is resistant only to OT-82. Together, these data suggest that acquired resistance to NAMPT inhibitors in RMS models involves the development of mutations in the target protein affecting drug binding and affinity."

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

Targeting nicotinamide metabolism with NAMPT-inhibitor OT-82 potentiates venetoclax in preclinical models of pediatric and adult acute myeloid leukemia (AACR 2026) - "In vivo, OT-82 potentiated venetoclax and venetoclax/azacitidine in a venetoclax-resistant pediatric AML cell line xenograft model, significantly extending survival of mice treated with OT-82/venetoclax or OT-82/venetoclax/azacitidine in comparison to the single agents or venetoclax/azacitidine. The OT-82 and venetoclax drug combination induced the most pronounced survival extensions, achieving maintained complete responses in 4/7 and 7/9 pediatric and adult AML PDXs, respectively, including high-risk cases and those with resistance to single agent venetoclax. In conclusion, this study establishes NAMPT inhibition by OT-82 as a promising metabolism-targeting strategy to overcome venetoclax resistance and supports clinical translation of OT-82 in combination with venetoclax in adult and pediatric AML."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • KMT2A • NAMPT • TP53

NAMPT inhibition impacts energy metabolism, induces DNA damage, and mediates tumor regression in preclinical neuroblastoma models [WITHDRAWN] (AACR 2025) - "We used two clinical NAMPTis under early phase study (OT-82 and KPT-9274) to validate our drug screen results in 10 molecularly diverse NB cell lines including 2 NB PDX-derived cell lines. Tissue studies from these experiments are ongoing and will be reported. Together, these data demonstrate that in NB, multiple critical pathways are impacted by the loss of NAD+ mediated by NAMPT inhibition and suggest NAMPTis may have translational potential as a novel agent against NB."

Preclinical • Neuroblastoma • Oncology • Solid Tumor • NAMPT

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

Impairing NAD+ synthesis is a powerful tool to increase the efficacy of the BTK inhibitor ibrutinib in Waldenström's macroglobulinemia. (ASH 2025) - "To test this the WM cell line BCWM1 was treated with the NAMPT inhibitor OT82 for 120h in a first step: 100% cellular death was achieved with 19.5nM OT82 in regular RPMI medium with a 4.9-fold increase in efficacy in Trp RPMI deficient medium. In conclusion, these data demonstrate that impairing intracellular NAD+ synthesis by concurrent NAMPT inhibition and Trp depletion is a powerful tool to increase the therapeutic activity of the BTKi Ibrutinib. They furthermore underline that Tryptophan can serve as an auxiliary source of NAD + for WM cells when intracellular NAMPT levels are limiting."

Clinical • B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Waldenstrom Macroglobulinemia • CXCR4 • MYD88 • NAMPT

Inhibition of nicotinamide metabolism by the novel NAMPT inhibitor OT-82 potentiates venetoclax in paediatric and adult acute myeloid leukaemia models (ASH 2025) - "Comparable synergy was also achieved with the NAMPT inhibitor KPT9274 in combination withvenetoclax. In vivo, OT-82 potentiated venetoclax and venetoclax/azacitidine in a venetoclax-resistantpaediatric AML cell line xenograft model, significantly extending survival of mice treated with OT-82/venetoclax or OT-82/venetoclax/azacitidine in comparison to the single agents orvenetoclax/azacitidine...This strategy offers a translationally actionableapproach to overcome resistance and improve outcomes for AML patients, particularly those withvenetoclax-resistant disease who currently face dismal survival rates. Collectively, this work highlightsNAMPT inhibition as a promising avenue to enhance venetoclax efficacy and paves the way for clinicaltranslation in both frontline and relapsed/refractory settings."

Clinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Pediatrics • BCL2 • CD34 • NAMPT • SIRPA

Targeting nicotinamide salvage pathway is a unique metabolic vulnerability of high-risk MDS stem cells (ASH 2025) - "Most of the proteinsenriched in MDS, such as G6PD, MDH1, ME2, IDH2, NADK2 and SIRT2, either maintain NAD(H) redoxbalance or use NAD as a cofactor for their function.To establish the role of NAD metabolism in MDS, we inhibited NAMPT, the rate-limiting enzyme in thenicotinamide salvage pathway of NAD anabolism, using small molecule inhibitors (KPT-9274 and OT82)and genetic approaches...Moreover, NAMPT-induced apoptosis inMDS was revealed to be synergistic with azacitidine, the current standard of care... Our data suggest that NAMPT is uniquely required for the function and survival of MDSHSPCs compared to normal and thus can be exploited as a promising therapeutic vulnerability. Theresults of this pre-clinical study provide strong support for initiating NAMPT inhibitor phase I/II clinicaltrials to improve outcomes for high-risk MDS patients."

Hematological Malignancies • Metabolic Disorders • Myelodysplastic Syndrome • CD34 • EIF4H • IDH2 • NAMPT • RRM2

Computational Discovery and Validation of NAD+ Biosynthesis As Unique Vulnerability in B-Lymphoid Malignancies (ASH 2023) - P1 | "Likewise, inhibitors of B-cell signaling (e.g. ibrutinib) and selective depletion of B-cells (e.g. rituximab, CD19 CAR-T cells) have achieved important progress and are well tolerated...To verify these results based on the DepMap dataset and our drug discovery tool (lymphoblasts.org), we studied the effects of seven NAMPT inhibitors (CAY10618, FK866, GMX1778, OT82, STF118804, STF31 and KPT9274) on a panel of myeloid leukemia and solid tumor cell lines as well as PDX from patients with B-ALL and mantle cell lymphoma... These findings highlight that the classical 'glucocorticoid paradigm' can be extended to discover novel vulnerabilities, including NAD+ biosynthesis. Computational integration of genetic and pharmacological compound screens was particularly powerful in identifying previously unrecognized opportunities to leverage selective vulnerabilities of B-lymphoid leukemia and lymphoma. Our genetic studies corroborate the unique role of NAMPT and NMNAT1 in..."

Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Metabolic Disorders • Oncology • Solid Tumor • ABL1 • BCR • NAMPT

Understanding the development of enzalutamide resistance based on a functional single-cell approach. (PubMed, bioRxiv) - "Single-cell RNA-Sequencing reveals heterogeneities of tumor cell populations. In most cases, however, the functional significance of the observed heterogeneity is not tested. In this study, we first identified a possible therapy-resistant prostate cancer cell subpopulation with scRNA-Seq, then confirmed the resistant phenotype with single cell and colony - based cloning and functional testing. In addition, we also identified a therapeutic vulnerability of the resistant cells."

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

Targeting NAD+ Metabolism Vulnerability in FH-Deficient Hereditary Leiomyomatosis and Renal Cell Carcinoma with the novel NAMPT Inhibitor OT-82. (PubMed, Mol Cancer Ther) - "OT-82 treatment of HLRCC xenograft tumors in vivo inhibited glycolytic flux as demonstrated by reduced lactate/pyruvate ratio in hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging experiments. Overall, our data define NAMPT inhibition as a potential therapeutic approach for FH-deficient HLRCC-associated renal cell carcinoma."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Uterine Leiomyoma • FH • NAMPT

A molecular circuit linking the BCR to the NAD biosynthetic enzyme NAMPT is an actionable target in Richter's syndrome. (PubMed, Blood Adv) - "Lastly, treatment of RS-PDX mice with the combination of PI3Ki and OT-82 results in significant inhibition of tumor growth, with evidence of in vivo activation of apoptosis. Collectively, these data highlight a novel application for NAMPT inhibitors in combination with BTKi or PI3Ki in aggressive lymphomas."

Journal • Hematological Malignancies • Lymphoma • Oncology • Richter's Syndrome • NAMPT • SIRT1

Inhibition of NAD+-dependent metabolic processes induces cellular necrosis and tumor regression in rhabdomyosarcoma models. (PubMed, Clin Cancer Res) - "RMS is highly vulnerable to NAMPT inhibition. These findings underscore the need for further clinical study of this class of agents for this malignancy."

Journal • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • NAMPT

Inhibition of NAD+-dependent metabolic processes induces cellular necrosis and tumor regression in rhabdomyosarcoma models (Clin Cancer Res) - "Most cell lines experienced profound depletion of ATP with subsequent irreversible necrotic cell death. Importantly, loss of NAD and glycolytic activity were confirmed in orthotopic in vivo models, which exhibited complete tumor regressions with OT-82 treatment delivered on the clinical schedule."

Preclinical • Oncology • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Exploiting metabolic vulnerabilities of pediatric rhabdomyosarcoma with novelnicotinamide phosphoribosyltransferase (NAMPT) inhibitor OT-82 (AACR 2023) - "NAMPT inhibition with OT-82 was highly effective in decreasing RMS proliferation and impairing glucose metabolism both in vitro and in vivo. Given these results, there is a critical need for further clinical study of this class of agents for RMS."

Clinical • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • NAMPT

Review of various NAMPT inhibitors for the treatment of cancer. (PubMed, Front Pharmacol) - "A few notable NAMPT specific inhibitors which have been produced include FK866, CHS828, and OT-82. This paper examines a number of cancer treatment methods which target NAMPT, including the usage of individual inhibitors, pharmacological combinations, dual inhibitors, and ADCs, all of which have demonstrated promising experimental or clinical results. We intend to contribute further ideas regarding the usage and development of NAMPT inhibitors in clinical therapy to advance the field of research on this intriguing target."

Journal • Review • Brain Cancer • Breast Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Glioma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • NAMPT

Evaluating the effects of critical metabolite depletion in pediatric rhabdomyosarcoma (RMS) using a novel inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). (ASCO 2022) - "In vitro and in vivo efficacy of OT-82 suggest that targeting NAD+ metabolism through NAMPT inhibition may be a promising approach for the treatment of RMS."

Clinical • Immunology • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • NAMPT

Evidence of a Synergistic Cross-Talk between the B Cell Receptor (BCR) and Nicotinamide Phosphoribosyl Transferase (NAMPT) in Richter’s Syndrome Patient-Derived Xenograft Models: Therapeutic Implications (ASH 2021) - "As NAMPT inhibitors (NAMPTi) we used both FK866 and OT-82, which are validated small molecules. These results highlight a crosstalk between BCR signalling and NAMPT/sirtuin axis in RS models, showing the increased efficacy of the dual targeting (i.e., PI3K-δ/γ and NAMPT), and supporting this novel and promising therapeutic strategy for the treatment of RS patients."

Preclinical • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • CASP3 • NAMPT

Effective targeting of NAMPT in patient-derived xenograft models of high-risk pediatric acute lymphoblastic leukemia. (PubMed, Leukemia) - "In addition, OT-82 enhanced the efficacy of the established drugs cytarabine and dasatinib and, as a single agent, showed similar efficacy as an induction-type regimen combining three drugs used to treat pediatric ALL. OT-82 sensitivity was associated with the occurrence of mutations in major DNA damage response genes, while OT-82 resistance was characterized by high expression levels of CD38. In conclusion, our study provides evidence that OT-82, as a single agent, and in combination with established drugs, is a promising new therapeutic strategy for a broad spectrum of high-risk pediatric ALL for which improved therapies are urgently needed."

IO Biomarker • Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics

OT-82, a novel anticancer drug candidate that targets the strong dependence of hematological malignancies on NAD biosynthesis. (PubMed, Leukemia) - "Hematopoietic and lymphoid organs were identified as the primary targets for dose limiting toxicity of OT-82 in both species. These results reveal strong dependence of neoplastic cells of hematopoietic origin on NAMPT and introduce OT-82 as a promising candidate for the treatment of hematological malignancies."

Journal • Burkitt Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Pediatrics

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) with OT-82 induces DNA damage, cell death, and suppression of tumor growth in preclinical models of Ewing sarcoma. (PubMed, Oncogenesis) - "Furthermore, combining low-dose OT-82 with low doses of agents augmenting DNA damage demonstrated enhanced antitumor activity in vitro and in vivo. Thus, OT-82 treatment represents a potential novel targeted approach for the clinical treatment of EWS."

Journal • Preclinical • Ewing Sarcoma • Oncology • Pediatrics • Sarcoma • Solid Tumor • NAMPT

International research collaboration reveals promising drug candidate for treatment of blood cancers (PRNewswire) - "OT82 demonstrated remarkable efficacy when used alone and was even more effective when used in combination with conventional treatments, thereby indicating promise for children with high-risk blood cancers....OT-82 is being tested in a clinical trial of adults with relapsed or refractory lymphoma. Following the successful completion of this trial, it is anticipated that the drug will proceed to clinical trial in children with high-risk acute lymphoblastic leukemia."

Clinical data • New trial