padnarsertib (KPT-9274) / Karyopharm, Antengene - LARVOL DELTA

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

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

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

Metabolism-Related Features Identify the Combination Metformin Plus NAMPT Inhibitors As a Selective Treatment Strategy in Acute Myeloid Leukemia (ASH 2023) - "In contrast, high mtDNAcn was not a predictive survival marker in a cohort of adult AML patients treated with venetoclax (VEN) + hypomethylating agents (HMA), indicating that these metabolic features are specifically linked to the resistance to intensive chemotherapy...Due to the link between mtDNAcn and mt complex I activity, we investigated if the treatment with metformin, known to inhibit complex I, would sensitize AML patients with high mtDNAcn to the standard of care AML drugs, such as Cytarabine (AraC), FLT3-inhibitors and VEN...Concomitantly, OXPHOS and glycolysis were diminished upon KPT-9274+metformin, suggesting that the combination was able to bypass the metabolic rewiring of the AML cells. In conclusion, we uncover a subgroup of patients with high mtDNAcn linked to increased mtOXPHOS that is resistant to chemotherapy-induced apoptosis and is characterized by poor clinical outcomes, which can be overcome by the inhibition of the mt complex I. Moreover, the..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CD34 • FLT3 • IDH1 • KIT • NAMPT

NAMPT Haploinsufficiency Is a Therapeutic Vulnerability in High-Risk Myeloid Malignancies (ASH 2023) - P1 | "Notably, NAMPT was the only essential gene on chromosome 7 with a first-in-class orally bioavailable inhibitor, KPT 9274, currently in clinical trials (NCT04914845)...In summary, our findings reveal NAMPT heterozygosity as a therapeutic vulnerability in high-risk myeloid neoplasms that warrants clinical follow-up. Further, we provide a framework centered on data-mining for uncovering collateral lethal genes in other cancers with recurrent chromosomal arm level deletions."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • 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

KNOWLEDGE DISCOVERY IN DATASETS: DRUGGABLE TARGETS FOR PANCREATIC DUCTAL ADENOCARCINOMA (UEGW 2025) - "Of note, EIF2A had high affinity to Padnarsertib (orally small molecular drug) with -11.4 kcal/mol, whereas STAMBP had affinity to Bemcentinib (orally small molecular drugs) with -11.8 kcal/mol, and ANXA2 and AHNAK2 to Zavegepant (CGRP receptor antagonist as migraine drug) with -12.1 kcal/mol and -11.4 kcal/mol, respectively, suggesting druggable targets on endocytosis/exocytosis/phagocytosis and CGRP signaling pathways. Potential druggable targets for PDAC were identified by KDD, particularly including the key proteins with repurposed drugs acting on the ERK/MAPK signaling pathway (involved CGRP) and the membrane fusion."

CNS Disorders • Migraine • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ACADSB • AHNAK2 • ANXA2 • ANXA3 • EIF2A • EIF2S1 • MYH14 • POLR2H • SPTAN1 • VIL1

Metabolic reprogramming represents a targetable mechanism to overcome acquired resistance to venetoclax in acute myeloid leukemia. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Targeting these metabolic changes with metformin (a mitochondrial complex I inhibitor) or KPT-9274 (a NAMPT inhibitor) re-sensitized resistant cells to venetoclax. Combination treatments showed strong synergy and near-complete cell elimination. These results highlight metabolic reprogramming as a heterogeneous but targetable resistance mechanism and support combining metabolic inhibitors with BCL2 blockade to treat refractory AML."

IO biomarker • Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • NAMPT • RPS6

Peripheral Blood Mononuclear Cell Gene Expression Signatures Predict Long-term Survivorship in Canine DLBCL. (PubMed, Res Sq) - "We recently completed a clinical trial in dogs with DLBCL using a combination of canine anti-CD20 antibody and low dose doxorubicin followed by one of three small molecule immune-modulating agents (KPT-9274, TAK-981 or RV1001). To facilitate point-of-care PBMC gene expression testing that could be used to distinguish those dogs likely to require more intensive treatment regimens in advance of relapse, we developed qPCR assays for TBHD, NPNT and ISG20 . Together these data provide proof of principle that biomarker interrogation in PBMCs can help predict early relapse and poor responders to inform clinical management of DLBCL."

IO biomarker • Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • DDX58 • MYC

KPT-9274 in Patients With Relapsed and Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: University of Colorado, Denver | Recruiting ➔ Active, not recruiting | Trial primary completion date: Feb 2026 ➔ Jul 2025

Enrollment closed • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

PAK4 phosphorylates and stabilizes MYC to promote acute myeloid leukemia. (PubMed, Cell Insight) - "Combining the PAK4 inhibitor KPT-9274 with the MCL-1 antagonist S63845 induces synergistic lethality in AML cells. These findings provide the mechanistic insight of MYC stabilization in AML and establish a PAK4 inhibition-based targeted strategy as a promising therapeutic approach for AML treatment."

Journal • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • T-cell Acute Lymphoblastic Lymphoma • FBXW7 • MCL1 • PAK4

NAMPT haploinsufficiency is a collateral lethal therapeutic vulnerability in high-risk myeloid malignancies with TP53 inactivation. (PubMed, Blood Neoplasia) - "Human acute myeloid leukemia (AML) cell lines with partial loss of NAMPT and primary samples from patients with -7 AML demonstrated heightened sensitivity to the NAMPT inhibitor KPT-9274 compared to control samples...These findings indicate that NAMPT heterozygosity is a therapeutic vulnerability in high-risk myeloid malignancies with -7/del(7q) and recommend NAMPT levels as a biomarker for NAMPT inhibitor sensitivity. This study also establishes a data-driven framework for identifying collateral lethal genes in cancers with recurrent chromosomal deletions."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • NAMPT • TP53

TARGETING NAMPT AND BTK IN MANTLE CELL LYMPHOMA: TP53-DEPENDENT SYNERGISTIC THERAPY (ICML 2025) - " We evaluated the effects of fourth-generation covalent/non-covalent BTK inhibitor LP-168 and NAMPT inhibitor KPT-9274 on MCL cell viability using CCK-8 cytotoxicity and flow cytometry apoptosis assays... Dual targeting of NAMPT and BTK achieves TP53 status-independent synergy, offering a novel strategy to overcome therapeutic resistance in MCL. These findings highlight the potential of this combination as a tailored therapy for relapsed/refractory patients."

IO biomarker • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • NAMPT • TP53 • TRAF1

Overcoming acquired venetoclax resistance in acute myeloid leukemia through cell metabolism targeting. (ASCO 2025) - "This study provides key insights into the mechanisms of venetoclax resistance in AML. Targeting cellular metabolism with metformin or KPT-9274, combined with venetoclax, offers promising synergistic effects and potential strategies to overcome resistance, improving treatment outcomes in resistant AML cases."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BBC3 • BCL2 • BCL2L1 • BCL2L10 • BCL2L11 • BECN1 • NAMPT • PMAIP1

Design, Synthesis, and Biological Evaluation of Selective PAK4 Degrader for the Treatment of Lung Tumor Metastasis. (PubMed, J Med Chem) - "To date , only PAK4 inhibitor KPT9274 is under clinical development with no detailed binding mechanism...Here, we report the development of CPS-021, a selective PAK4 degrader derived from our previously reported compound CPL-042 conjugated to pomalidomide...Our findings provide evidence that the selective PAK4 degrader exhibits significant pharmacological effects in suppressing cancer cell migration and invasion. These results support the further development of CPS-021 as a valuable tool compound for conducting in-depth biological investigations of group II PAKs."

Journal • Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

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 • CNS Tumor • 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

Inhibition of NAMPT by PAK4 Inhibitors. (PubMed, Int J Mol Sci) - "KPT-9274, a PAK4 inhibitor, significantly reduces the growth of triple-negative breast cancer cells and mammary tumors in mouse models, and it also inhibits the growth of several other types of cancer cells...Molecular docking studies were also used to help us better understand the mechanism by which PAK4 inhibitors block PAK4 and NAMPT activity, and we identified specific residues on the PAK4 inhibitors that interact with NAMPT and PAK4. Our results suggest that PAK4 inhibitors may have a more complex mechanism of action than previously understood, necessitating further exploration of how they influence cancer cell growth."

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

Inhibition of NAMPT by PAK4 Inhibitors. (Multidisciplinary Digital Publishing Institute) - "KPT-9274, a PAK4 inhibitor, significantly reduces the growth of triple-negative breast cancer cells and mammary tumors in mouse models, and it also inhibits the growth of several other types of cancer cells. Interestingly, although it was first identified as a PAK4 inhibitor, KPT-9274 was also found to inhibit the enzyme NAMPT (nicotinamide phosphoribosyltransferase), which is crucial for NAD (nicotinamide adenine dinucleotide) synthesis and vital for cellular energy and growth....Our findings confirm that multiple PAK4 inhibitors also inhibit NAMPT activity. This was assessed both in cell-free assays and in a breast cancer cell line. Molecular docking studies were also used to help us better understand the mechanism by which PAK4 inhibitors block PAK4 and NAMPT activity, and we identified specific residues on the PAK4 inhibitors that interact with NAMPT and PAK4."

Preclinical • Oncology • Triple Negative Breast Cancer

Orphan Designation: treatment of Ewing sarcoma (FDA) - Date Designated: 07/09/2024

Orphan drug • Ewing Sarcoma

Orphan Designation: Treatment of soft tissue sarcoma (FDA) - Date Designated: 07/08/2024

Orphan drug • Soft Tissue Sarcoma

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

TEACH: A Study of Evaluating Dual Inhibitor of PAK4 and NAMPT ATG-019 in Advanced Solid Tumors or Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P1 | N=20 | Terminated | Sponsor: Antengene Therapeutics Limited | N=70 ➔ 20 | Recruiting ➔ Terminated; Because the sponsor modified the study-product development strategy.

Enrollment change • Metastases • Trial termination • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Targeting NAD+ metabolism: Pre-clinical insights into potential cancer therapy strategies. (PubMed, Endocrinology) - "NAMPT inhibition (alone or in combination with other cancer therapies, including endocrine therapy and chemotherapy) results in decreased cell viability and tumor burden for many cancer types. Many NAMPT inhibitors (NAMPTi) tested before were discontinued due to toxicity; however, a novel NAMPTi, KPT-9274, is a promising, low-toxicity option currently in clinical trials."

Journal • Preclinical • Oncology • NAMPT • PARP1

Dual-inhibition of NAMPT and PAK4 induces anti-tumor effects in 3D-spheroids model of platinum-resistant ovarian cancer. (PubMed, Cancer Gene Ther) - "Moreover, the compound reduced PAK4 activity by altering its mostly cytoplasmic localization, leading to NAD+-dependent decreases in phosphorylation of S6 Ribosomal protein, AKT, and β-Catenin in the cytoplasm. These findings suggest that KPT-9274 could be a promising treatment for ovarian cancer patients who are resistant to platinum drugs, emphasizing the need for precision medicine to identify the specific NAD+ producing pathway that a tumor relies upon before treatment."

Journal • Oncology • Ovarian Cancer • Solid Tumor • CTNNB1 • NAMPT • PAK4