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

NAMPT inhibition impacts energy metabolism, induces DNA damage, and mediates tumor regression in preclinical neuroblastoma models (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NAMPT inhibitor-resistant rhabdomyosarcoma models exhibit alterations in metabolic and genomic profiles [WITHDRAWN] (AACR 2025) - "Treatment with the clinical NAMPT inhibitor OT-82 results in complete tumor regressions in vivo, however, upon intermittent treatment, acquired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

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 Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • CXCR4 • IFNG • IL2RA • LGALS3 • NAMPT • NQO1

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

Monosomy 7/del(7q) Cause Sensitivity to Inhibitors of Nicotinamide Phosphoribosyltransferase in Acute Myeloid Leukemia. (PubMed, Blood Adv) - "Furthermore, the combination of the BCL2 inhibitor venetoclax and the NAMPT inhibitor KPT-9274 resulted in the death of significantly more leukemic blasts in AML samples with -7/-7q compared to the NAMPT inhibitor alone. In conclusion, our findings demonstrate that AML with -7/-7q are highly sensitive to NAMPT inhibition, suggesting that NAMPT inhibitors have the potential to be an effective targeted therapy for patients with monosomy 7 or del(7q)."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • NAMPT

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 • Transplantation • BCL2 • CD34 • FLT3 • IDH1 • KIT • NAMPT

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

Anticancer efficacy of KRASG12C inhibitors is potentiated by PAK4 inhibitor KPT9274 in preclinical models of KRASG12C mutant pancreatic and lung cancers. (PubMed, Mol Cancer Ther) - "KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C-mutant tumors. Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for cancer patients who do not respond or develop resistance to KRASG12C inhibitor treatment."

Journal • Preclinical • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

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

PAK4 inhibition significantly potentiates Gemcitabine activity in PDAC cells via inhibition of Wnt/β-catenin, p-ERK/MAPK and p-AKT/PI3K pathways. (PubMed, Biochem Biophys Rep) - "PAK4 inhibition by KPT-9274 led to significant potentiation of Gemcitabine activity in PDAC cells, with an increase in apoptosis, DNA damage and cell cycle arrest. Our data unravel probable molecular mechanisms behind combination of PAK4 inhibition with Gemcitabine to counter PDAC, which may be unequivocally proved further with knock down of PAK4. Our findings provide a strong rationale to exploit the combination therapy of Gemcitabine and PAK4 inhibitor for PDAC at pre-clinical and clinical levels."

Journal • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CTNNB1 • JUN • KRAS • MYC • PAK4 • RRM2

Baseline tumor gene expression signatures correlate with chemoimmunotherapy treatment responsiveness in canine B cell lymphoma. (PubMed, PLoS One) - "The dogs in this study were part of a larger clinical trial evaluating the use of combinations of doxorubicin chemotherapy, anti-CD20 monoclonal antibody, and one of three small molecule inhibitors: KPT-9274, TAK-981, or RV1001. Trends for selected candidate biomarker genes were confirmed via qPCR. Our findings emphasize the heterogeneity in DLBCL, similarities and differences between canine and human DLBCL, and ultimately identify biomarkers that may help guide the choice of chemoimmunotherapy treatment in dogs."

IO biomarker • Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND3 • CD36 • CDKN1A • CREBBP • NRAS • PIK3CD • PTEN • TLR3

KPT-9274 in Patients With Relapsed and Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: University of Colorado, Denver | Suspended ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

KPT-9274 in Patients With Relapsed and Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=40 | Suspended | Sponsor: University of Colorado, Denver | Recruiting ➔ Suspended

Trial suspension • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

NAD + Metabolism Generates a Metabolic Vulnerability in Endocrine-Resistant Metastatic Breast Tumors in Females. (PubMed, Endocrinology) - "A synergistic effect was not observed when KPT-9274 was combined with palbociclib or tamoxifen or when Fulv was combined with other metabolic inhibitors. We show that NAMPT inhibitor KPT-9274 and fulvestrant (Fulv) works synergistically to reduce metastatic tumor burden...Targeting metabolic adaptations in endocrine-resistant metastatic breast cancer is a novel strategy, and alternative approaches aimed at improving the therapeutic response of metastatic ER+ tumors are needed. Our findings uncover the role of ERα-NAMPT cross-talk in metastatic breast cancer and the utility of NAMPT inhibition and antiestrogen combination therapy in reducing tumor burden and metastasis, potentially leading to new avenues of metastatic breast cancer treatment."

Journal • Metastases • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • NAMPT

PAK4-NAMPT dual inhibition as a feasible strategy for treatment of resistant pancreatic neuroendocrine tumors (AACR 2018) - P1; "In this study, pNET cell lines QGP-1 and Bon-1 were subjected to either PAK4 RNA interference (RNAi), PAK4-NAMPT dual inhibitors (the clinical compound KPT-9274 or an analog KPT-7523) or the PAK4 specific inhibitor, PF-3738309 and NAMPT specific inhibitor FK866 in the presence or absence of mTOR inhibitors (everolimus or INK128). KPT-9274 is currently in a Phase I trial of patients with advance solid malignancies or NHL . Our pre-clinical work establishes a solid rationale for a Phase II clinical study of KPT-9274 and an mTOR inhibitor combination for the treatment of difficult to treat pNETs."

Gastrointestinal Cancer • Neuroendocrine Tumor • Non-Hodgkin’s Lymphoma

Sensitivity to NAMPT inhibition: In vitro and in vivo characterization in ovarian cancer (AACR 2023) - "Previous in vitro work on determining the unique sensitivities of various cancers to nicotinamide phosphoribosyltransferase inhibitors (NAMPTis) has demonstrated promising effects of treating cancer cells with NAMPTis such as FK866 and KPT9274. In addition to a synergistic growth inhibitory response in ovarian cancer cells, preclinical combination studies of NAMPTis with olaparib, an approved PARP inhibitor, exhibited higher levels of DNA damage accumulation than with single drug treatments. Our in vitro and in vivo characterizations of NAMPT inhibition suggest that NAMPTis as either single agents or in combination treatments with PARP inhibitors should be investigated further as potential treatment options for ovarian cancer patient populations."

Preclinical • Oncology • Ovarian Cancer • Solid Tumor • HRD • NAMPT

[PREPRINT] Anticancer efficacy of KRASG12C inhibitors is potentiated by PAK4 inhibitor KPT9274 in preclinical models of KRASG12C mutant pancreatic and lung cancers (bioRxiv) - "Oral administration of a suboptimal dose of KPT9274 in combination with sotorasib (at one fourth of MTD) demonstrated significant inhibition of the tumor burden (p = 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model where KPT9274, acting as an adjuvant, prevented tumor relapse following the discontinuation of sotorasib treatment (p = 0.0001). KPT9274 and sotorasib combination also resulted in enhanced survival. This is the first study showing that KRASG12C inhibitors can synergize with PAK4 inhibitor KPT9274 both in vitro and in vivo resulting in remarkably enhanced antitumor activity and survival outcomes."

Preclinical • Preprint • Gastrointestinal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Dual Targeting PAK4 and NAMPT As a Novel Therapeutic Approach for Aggressive Non-Hodgkin’s Lymphoma (ASH 2021) - P1 | "Similar results were obtained with positive controls PAK4 [PF-3578309] and NAMPT specific inhibitors [FK-866]...We then showed KPT-9274 to synergize with the standard of care chemotherapy cyclophosphamide, vincristine, and adriamycin used for NHL management (decreased IC25 and IC50 in several combination treatments)...The anti-tumor potential of KPT-9274 ± niacin in several aggressive lymphoma models strongly supports its efficacy in this setting. It strengthens our phase I study design to evaluate safety and tolerability and anti-tumor activity in patients with advanced solid malignancies or NHL (NCT02702492)."

IO biomarker • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Transplantation • BCL2 • CASP3 • CASP9 • CCND1 • CTNNB1 • NAMPT • PAK4 • VCL