GMX1778 / Teva - LARVOL DELTA

Combined inhibition of NAD synthesis and C-terminal binding protein cooperatively induces cell death and inhibits growth of high grade serous ovarian carcinoma. (PubMed, Sci Rep) - "Highlighting translational potential in late-stage HGSOC, combined JW-98/GMX1778 treatment of platinum-resistant OVCAR3 HGSOC mouse xenografts abrogated tumor growth without observable toxicity. Combined inhibition of CtBP and NAD synthesis represents a novel therapeutic strategy that could improve outcomes in chemoresistant HGSOC."

Journal • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CASP8 • CTBP1

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

Comprehensive Drug Profiling and CRISPR Screening Reveal Essential Pathways for NK Cell Cytotoxicity (ASH 2024) - "In addition, pevonedistat, daporinad, and bryostatin 1 enhanced NK cell activity, whereas sotrastaurin showed strong NK cell-inhibiting effects...Various NAMPT inhibitors (KPT-9274, GMX1778 and LSN3154567) not included in the original screens showed similar effects to daporinad in AML and ALL cell lines...In conclusion, our study identifies PKC, NAMPT, and NEDD8 having an essential role in controlling NK cell-mediated killing and suggests potential compounds to enhance NK cell effectiveness in treating hematological malignancies. These findings offer insights into developing combination immunotherapy strategies to improve treatment outcomes."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Myeloid Leukemia • Diffuse Large B Cell Lymphoma • Gene Therapies • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • CXCR4 • IFNG • IL2RA • LGALS3 • NAMPT • NQO1

Differential Mitochondrial Redox Responses to the Inhibition of NAD+ Salvage Pathway of Triple Negative Breast Cancer Cells. (PubMed, Cancers (Basel)) - "Additionally, the redox state was found fully recovered after removing the Nampt inhibitor. This study supports the utility of ORI in rapid metabolic phenotyping of TNBC cells under NAD-deficient stress to identify responsive cells and biomarkers of treatment response, facilitating combination therapy strategies."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • NAMPT

Glioblastoma Sensitization to Therapeutic Effects by Glutamine Deprivation Depends on Cellular Phenotype and Metabolism. (PubMed, Biochemistry (Mosc)) - "Here we investigated the effect of glutamine deprivation on cellular metabolism and sensitivity of human glioblastoma cells U87MG and T98G to drugs of various origin: alkylating cytostatic agent temozolomide; cytokine TRAIL DR5-B - agonist of the DR5 receptor; and GMX1778 - a targeted inhibitor of the enzyme nicotinamide phosphoribosyltransferase (NAMPT), limiting NAD biosynthesis. Thus, phenotypic and metabolic differences between the two human glioblastoma cell lines caused divergent metabolic changes and contrasting responses to different targeted drugs during glutamine deprivation. These data should be considered when developing treatment strategies for glioblastoma via drug-mediated deprivation of amino acids, as well as when exploring novel therapeutic targets."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CD133 • NAMPT • TNFRSF10B

NAMPT INHIBITORS TARGET MYELOBLASTS FROM HIGH-RISK MDS PATIENTS WITH MONOSOMY 7 OR DELETION 7Q (EHA 2024) - "Survival with the current standard oftreatment consisting of hypomethylating agents azacytidine and decitabine remains dismal (1...Viably frozen BM MNCs from MDS patients with(n=7) and without (n=7) -7/-7q were thawed and incubated with up to 10 drugs, including four NAMPTinhibitors (daporinad, GMX1778, KPT9274 and LSN3154567), in seven concentrations for 72h... Our results show that NAMPT inhibitors are active in high-risk MDS patient samples, specifically in thosesamples that have -7/-7q aberrations. This increased sensitivity of -7/-7q to NAMPT inhibition could beexplained by haploinsufficient gene expression of NAMPT. These results indicate that NAMPT inhibitors couldbe worth investigating in a larger cohort of high-risk MDS patients and in combination with clinically relevantinhibitors such as azacytidine and venetoclax."

Clinical • IO biomarker • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CD34 • NAMPT

Exploiting Metabolic Defects in Glioma with Nanoparticle Encapsulated NAMPT Inhibitors. (PubMed, Mol Cancer Ther) - "Finally, we show that CED of NP-encapsulated GMX1778 to NAPRT-silenced intracranial GBM xenografts in mice exhibit significant tumor growth delay and extends survival. These data support an approach to treat gliomas harboring defects in NAD+ metabolism using CED of NP-encapsulated NAMPTis to greatly improve the therapeutic index and treatment efficacy for this class of drugs."

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

Orthogonal targeting of NAD metabolism and ErbB2/ErbB3 signaling in pancreatic adenocarcinoma (AACR 2024) - "Moreover, we show that the majority of PDAC cells with high levels of ErbB3 expression are uniquely sensitive to the ErbB2-targeted tyrosine kinase inhibitor lapatinib...Upon depletion of NAD using the NAD salvage pathway inhibitor GMX1778 in human PDAC cells, we observed a striking coordinate decrease in the levels of both ErbB2 and ErbB3... Our findings highlight the novel connection between NAD and ErbB2/3 in PDAC. Furthermore, our data suggests combining chemical or biologic inhibitors of ErbB2/3 with an inhibitor of NAD synthesis may result in highly synergistic cytotoxic effects in PDAC cells and PDAC preclinical models. Such data could support the future development of a human PDAC clinical trial repurposing agents targeting NAD synthesis and ErbB2/3 that are already FDA-approved or currently in clinical testing."

Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • EGFR • ERBB3 • HER-2

Racial/ethnic differences of pediatric brain tumors in patient derived orthotopic xenograft (PDOX) model development and drug responses detected by high-throughput drug screening (SNO 2023) - "Compared with 38 active drugs in White children (i.e., privately active drugs, including Bortezomib, YM155, Carfilzomib, Daporinad, GMX-1778, Dalanzomib, Cucurbitacin, Bafilomycin, Vincristin and Mitoxantrone), the number was 0 for Hispanic children. Our data indicates a significant difference in drug response across different racial/ethnic groups and provides a strong rationale for additional examination of those differences with broader coverage of tumors."

Clinical • Brain Cancer • CNS Tumor • Glioma • Medulloblastoma • Oncology • Pediatrics • Solid Tumor

Combined targeting of NAD biosynthesis and the NAD-dependent transcription factor C-terminal Binding Protein as a promising novel therapy for pancreatic cancer. (PubMed, Cancer Res Commun) - "Indeed, depletion of cellular NAD via the NAMPT inhibitor GMX1778 enhanced growth inhibition induced by either RNAi-mediated CtBP1/2 knockdown or the CtBP dehydrogenase inhibitor 4-chlorophenyl-2-hydroxyimino propanoic acid as much as 10-fold in PDAC cells, while untransformed pancreatic ductal cells were unaffected...Moreover, this same therapeutic combination strongly attenuated growth of PDAC cell line xenografts in immunodeficient mice, with no observable toxicity. Collectively, our data demonstrate that targeting CtBP in combination with NAD depletion represents a promising therapeutic strategy for PDAC."

Journal • Gastrointestinal Cancer • Hepatology • Metabolic Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CTBP1 • CTBP2 • NAMPT • TIAM1

Targeting of Glucose Transport and the NAD Pathway in Neuroendocrine Tumor (NET) Cells Reveals New Treatment Options. (PubMed, Cancers (Basel)) - "(2) the proliferation and survival rate of tumor cells was significantly affected by the GLUT-inhibitors fasentin and WZB1127, as well as by the NAMPT inhibitors GMX1778 and STF-31...As previously shown for STF-31 in a panel NET-excluding tumor cell lines, both drugs specifically inhibited glucose uptake at higher (50 μM), but not at lower (5 μM) concentrations. (4) our data suggest that GLUT and especially NAMPT inhibitors are potential candidates for the treatment of NET tumors."

Journal • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • NAMPT

Monosomy 7 and Del(7q) Cause Selective Sensitivity to Inhibitors of Nicotinamide Phosphoribosyltransferase in Acute Myeloid Leukemia (ASH 2022) - "To further support our findings, we analyzed the sensitivity of AML cells without or with -7/-7q to four NAMPT inhibitors (daporinad, GMX1778, KPT-9274, and LSN3154567) using multiparametric flow cytometry...Interestingly, the analysis of ex vivo drug sensitivities also revealed that while the majority of AML with -7/-7q are resistant to the FDA-approved BCL2 inhibitor venetoclax, they are highly sensitive to daporinad (Figure A)...In conclusion, we have found that AML with NAMPT haploinsufficiency caused by -7/-7q shows selective sensitivity to NAMPT inhibition. This suggests that NAMPT inhibitors have the potential to be a potent targeted therapy for AML with -7/-7q, a disease with a particularly adverse prognosis."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • CD14 • CD34 • KIT • NAMPT • PTPRC

Different Effects of RNAi-Mediated Downregulation or Chemical Inhibition of NAMPT in an Isogenic IDH Mutant and Wild-Type Glioma Cell Model. (PubMed, Int J Mol Sci) - "Given this dependence of IDH1 cells on NAMPT expression, we explored the effects of the NAMPT inhibitors FK866, GMX1778 and GNE-617. Surprisingly, these agents were equally cytotoxic to IDH1 and IDH1 cells. Altogether, our results indicate that targeting the NAD synthesis pathway is a promising therapeutic strategy in IDH mutant gliomas; however, the agent should be carefully considered since three small-molecule inhibitors of NAMPT tested in this study were not suitable for this purpose."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • IDH1 • NAMPT

Exploiting mutant PPM1D-induced metabolic defects with nanoparticle-encapsulated NAMPT inhibitors (AACR 2022) - "Thus far, we have fabricated and optimized PLA-PEG copolymeric nanoparticles capable of encapsulating the NAMPTi, GMX-1778...Lastly, these NAMPTi-NPs display prolonged retention in brain tissue compared to free drug injection over time. With further in vivo validation, this NP-based strategy will be a powerful tool for targeting mutant PPM1D DIPG and other cancers."

Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor • NAMPT • PPM1D

[VIRTUAL] Nanoparticle-Encapsulated NAMPT Inhibitors Administered via Convection Enhanced Delivery as a Novel Glioma Radiosensitization Strategy (ASTRO 2020) - " The NAMPTi GMX-1778 was efficiently encapsulated into NPs (GMX-NP) with multiple polymers (e.g. PLA-PEG, PLA-HPG, and PLGA) with yields of 68-82%... This work successfully developed a NP-encapsulated NAMPTi with in vitro efficacy and in vivo safety and stability. Additional studies will continue to refine and characterize these formulations as well as assess in vivo efficacy. These data lay the groundwork for future combinations of NAMPTi NPs with RT."

Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • NAMPT • PPM1D