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

Computational Identification of New Dual PAK4 and NAMPT Inhibitors. (PubMed, Int J Mol Sci) - "While existing inhibitors such as KPT9274 and PF-3758309 have demonstrated preclinical activity, their clinical translation has been limited by poor selectivity, suboptimal efficacy, and dose-limiting toxicities. Expanding the pool of dual inhibitors enhances opportunities for preclinical development, supports optimization of pharmacokinetic and safety profiles, and strengthens datasets for drug discovery. Collectively, this work broadens the landscape of dual PAK4 and NAMPT inhibitors and supports their potential application across multiple cancer types beyond triple-negative breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • NAMPT • PAK4

Targeting p21-activated kinase 4: Recent advances in the discovery of PAK4 inhibitors and strategies for isoform selectivity. (PubMed, Eur J Med Chem) - "We also summarize the potential ADMET liabilities-such as pronounced efflux, metabolic instability, and poor oral bioavailability-that may arise from structural modifications aimed at enhancing PAK4 selectivity, and discuss rational optimization strategies to navigate these inherent barriers. Finally, we discuss clinical lessons from PF-3758309 and KPT-9274/padnarsertib and highlight how allosteric inhibitors and PROTAC degraders may help address limitations of conventional ATP-site inhibitors."

Journal • Review • Metabolic Disorders • Oncology • Targeted Protein Degradation • PAK4

PAK4 in the Tumor Immune Microenvironment: Biological Functions, Regulatory Mechanisms, and Targeted Therapeutic Strategies. (PubMed, Med Res Rev) - "Small-molecule PAK4 inhibitors (e.g., KPT-9274, PF-3758309, compound 55) and degraders (e.g., CPS-021) effectively suppress tumor growth in preclinical models. Elevated PAK4 expression correlates significantly with poor patient prognosis and resistance to immunotherapy, positioning it as both a predictive biomarker and a promising therapeutic target. Elucidating the PAK4-TME axis provides a mechanistic foundation for developing novel combinatorial strategies targeting the tumor microenvironment."

IO biomarker • Journal • Review • Metabolic Disorders • Oncology • HIF1A • PAK4

Structural basis for a p21-activated kinase 4 and nicotinamide phosphoribosyltransferase dual inhibitor. (PubMed, Acta Crystallogr D Struct Biol) - "KPT-9274, a clinical stage compound, has been reported as a dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT), but its structural basis has remained undefined...Biophysical assays revealed distinct affinities across the two targets. These findings highlight the 2-aminopyridine moiety as a versatile pharmacophore that is adaptable to structurally unrelated proteins and provide a framework for designing next-generation dual inhibitors in cancer therapy."

Journal • Oncology • NAMPT • PAK4

NAMPT haploinsufficiency is a therapeutic vulnerability to NAMPT inhibition in -7/-7q MDS. (PubMed, Biomark Res) - "The NAMPT inhibitor KPT-9274 combined with BCL2 inhibitor venetoclax was particularly effective at targeting MDS blasts compared to NAMPT inhibition alone. MDS samples with -7/-7q also showed significantly lower NAMPT expression compared to the non -7/-7q samples, indicative of haploinsufficient gene expression profile. In conclusion, these findings support NAMPT haploinsufficiency as a vulnerability and as biomarker for NAMPT inhibitor activity in -7/-7q MDS."

IO biomarker • Journal • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CD34 • 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

PAK4 inhibition enhances tumor immunity by inducing viral mimicry (AACR 2026) - "In vivo, PAK4 knockdown or treatment with clinically available PAK4 inhibitor KPT-9274 significantly suppressed tumor growth and enhanced intratumoral infiltration of CD8⁺ T cells and natural killer (NK) cells. Clinically, PAK4 expression inversely correlated with LINE1-ORF1 levels in patient tumor samples, and lower PAK4 expression associated with improved patient survival. These findings identify PAK4 as a key regulator of SUV39H1 and REs, and promising therapeutic target in cancer."

Late-breaking abstract • Oncology • CD8 • STING • SUV39H1

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

Peripheral blood mononuclear cell gene expression signatures predict long-term survivorship in canine DLBCL. (PubMed, Sci Rep) - "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

First-in-Human Phase I Study of KPT-9274, a First-in-Class Dual Inhibitor of PAK4 and NAMPT, in Patients with Advanced Solid Malignancies. (PubMed, Target Oncol) - P1 | "The MTD of KPT-9274 was not reached in a dose escalation study conducted in patients with advanced solid tumors. Clinical activity was not observed at study doses in combination with niacin or nivolumab. Further investigation into potential therapeutic areas where KPT-9274 may serve as a targeted agent is warranted."

First-in-human • Journal • P1 data • Fatigue • Hematological Disorders • Melanoma • Musculoskeletal Pain • Oncology • Solid Tumor • NAMPT

MTFP1 drives pancreatic cancer liver metastatic colonisation by regulating mitochondrial metabolism reprogramming. (PubMed, Gut) - "Our data demonstrate that the enhanced MTFP1 expression leads to an upregulated glutamine-OXPHOS axis in PDAC liver colonisation. This metabolic shift is triggered by the ROS/PI3K/AKT/c-MYC/SLC1A5 pathway. Targeting MTFP1 may be a potential therapeutic strategy for PDAC patients with liver metastasis."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • MYC • SLC1A5

KPT-9274 in Patients With Relapsed and Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: University of Colorado, Denver | Active, not recruiting ➔ Completed | N=40 ➔ 16 | Trial completion date: Feb 2027 ➔ Oct 2025

Enrollment change • Trial completion • Trial completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Inhibition of NAMPT targets DNA damage response to sensitize alkylating chemotherapy in TP53 mutant mantle cell lymphoma. (PubMed, Blood Adv) - "The NAMPT inhibitor KPT-9274 reduced viability and induced apoptosis in MCL cells irrespective of TP53 status...Our findings establish NAMPT as a dual-context therapeutic node, providing a precision medicine framework to circumvent chemoresistance in high-risk MCL. These results advocate for the clinical evaluation of TP53 status-guided NAMPT inhibitor combinations to address this unmet oncologic challenge."

Journal • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • NAMPT • TP53

NAMPT inhibition uncovers therapeutic vulnerabilities to venetoclax and chemotherapy in acute myelogenous leukemia. (PubMed, Leuk Lymphoma) - "Proteomic profiling showed that NAMPT inhibition with KPT-9274 induced adaptive upregulation of BCL2, an anti-apoptotic protein, highlighting a survival mechanism...Additionally, NAMPT inhibition reduced PARP activity and impaired DNA repair pathways, sensitizing AML cells to cytarabine and hypomethylating agents. Together, these results demonstrate that NAMPT inhibition both potentiates venetoclax activity and enhances the cytotoxic effects of standard chemotherapies by targeting metabolic and DNA repair vulnerabilities. These findings provide strong preclinical support for evaluating NAMPT and BCL2 dual inhibition strategies in future AML clinical trials."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • BCL2L1 • MCL1 • NAMPT

Metabolic reprogramming drives acquired venetoclax resistance in Acute Myeloid Leukemia and reveals targetable vulnerabilities (ASH 2025) - "In addition, we tested the therapeutic potential of combining venetoclax with metabolic inhibitors, metformin, a mitochondrial complex I inhibitor, and KPT-9274, a NAMPT inhibitor, by calculating synergy scores and quantifying apoptotic responses. These findings support a combinatorial therapeutic strategy targeting both apoptotic and metabolic pathways to overcome acquired venetoclax resistance in AML. Supported by FAPESP, CAPES, and CNPq."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • ANXA5 • BAX • BBC3 • BCL2L1 • BCL2L11 • BID • MCL1 • NAMPT • PMAIP1 • RPS6

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

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