tomivosertib (eFT508) / eFFECTOR Therap - LARVOL DELTA

Type I interferons enhance human dorsal root ganglion nociceptor excitability and induce TRPV1 sensitization. (PubMed, JCI Insight) - "Type I IFNs prolong the duration of capsaicin responses, an effect that is blocked by inhibition of MNK1/2 with eFT508, a specific inhibitor of these kinases. This study supports the conclusion that type I IFNs induce hyperexcitability and TRPV1-sensitization when they interact with IFNAR1/2 in hDRG nociceptors."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Musculoskeletal Pain • Neuralgia • Pain • Rheumatoid Arthritis • Rheumatology • EIF4E • IFNA1 • IFNAR1 • IFNAR2 • IFNB1 • STAT1 • TRPV1

Activation-independent polypeptide synthesis contributes to platelet immune response to a-hemolysin (ISTH 2025) - "Both platelet lysates and platelet releasates showed increased protein content within 2 hours of exposure to sub-activating concentrations of Hla. Increased protein levels were translation initiation signal-dependent, as they were abolished with eFT-508, an inhibitor of essential translation initiation signaling kinases MNK1/2."

Infectious Disease

Suppressed pain signaling in recessive dystrophic epidermolysis bullosa with a MNK1/2 inhibitor (SID 2025) - "RDEB patients experience neuropathic pain, exacerbated during dressing changes and treated largely with morphine and gabapentin. Mouse pain behaviors (excessive grooming, paw nibbling, and facial grimacing) were observed, and duration of pain behavior was significantly decreased (50%; p<0.05) in RDEB mice treated with the MNK inhibitor versus vehicle control. Our preliminary findings identify a basis for pain in RDEB and implicate targeting the MNK pathway with tomivosertib as a new therapeutic direction in RDEB management."

Inflammation • Neuralgia • Pain • COL7A1 • EIF4E • IL4R • IL6R

Overcoming stress induced therapy resistance in triple negative breast cancer with the MNK inhibitor EB1 (AACR 2025) - "Main results obtained with EB1 were compared to the siRNA mediated knock-down of MNKs and eFT-508 (eFFECTOR Therapeutics, Inc.) as the most advanced Type I MNK inhibitor.RESULTS...We propose that EB1 might represent a novel therapeutic opportunity, to combat cellular stress induced therapy resistance. This might be of particular importance for the treatment of TNBC, in which good initial responses to systemic therapies are in most of cases followed by therapy resistance and tumor relapse."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EIF4E

Morpholino nicotinamide analogs of ponatinib, dual MNK, p70S6K inhibitors, display efficacy against lung and breast cancers. (PubMed, Bioorg Chem) - "HSND80 has a longer target residence time (τ) of 45 mins and 58 mins against MNK1 and MNK2 respectively, compared to τ of eFT508 (tomivosertib) against MNK1 and MNK2 (τ = 1 min and 5 min, respectively). Western blotting analysis and phosphoproteomics analysis of the TNBC cell line, MDA-MB-231, revealed that phosphorylations of elF4E (MNK target) and elF4B and S6 (p70S6K targets) were reduced upon compound treatment, which is in line with the proposed mechanism of action; dual MNK/p70S6K targeting. HSND80 could be dosed orally at 15 and 30 mg/kg and at such doses, could reduce tumor volume in a syngeneic NSCLC mouse model."

Journal • Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

TSC2 loss in neural progenitor cells suppresses mRNA translation of neurodevelopmental genes. (PubMed, Brain) - "Importantly, translation of these ASD- and NDD-associated genes was reversed upon inhibition of either mTORC1 or MNK1/2 signaling using RMC-6272 or eFT-508, respectively. This study establishes the importance of mTORC1-eIF4F- and MNK-eIF4E-sensitive mRNA translation in TAND, ASD and other neurodevelopmental disorders laying the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for these disorders."

Journal • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation • Oncology • Psychiatry • EIF4E • EIF4G1 • TSC1 • TSC2

Critical Role of the MNK/eIF4E Pathway in Airway Remodeling in Chronic Allergic Asthma (AAAAI-WAO 2025) - "Conclusions This study elucidates the MNK/eIF4E pathway's role in airway remodeling and underscores eFT-508's potential as a therapeutic agent for chronic allergic asthma. The findings support further investigation of eFT-508, which is currently in use for cancer trials, as a novel approach to managing airway inflammation and remodeling in chronic allergic asthma."

Asthma • Immunology • Oncology • Respiratory Diseases • EIF4E

Phase Ib Pharmacodynamic Study of the MNK Inhibitor Tomivosertib (eFT508) Combined With Paclitaxel in Patients With Refractory Metastatic Breast Cancer (Clin Cancer Res) - P1b | N=19 | NCT04261218 | "Tomivosertib alone and in combination with paclitaxel was well tolerated. There was no pharmacokinetic interaction between the drugs. We observed a clear reduction in phosphorylation of eIF4E at S209, a major substrate of MNK1/2, and identified tomivosertib-induced perturbations in the proteome, translatome, and cellular populations of biopsied metastatic breast cancer tissue."

P1 data • Breast Cancer

A patent review of mitogen-activated protein kinase-interacting kinases (MNKs) modulators (2019-present). (PubMed, Expert Opin Ther Pat) - "The majority of small-molecule inhibitors developed recently, similarly to the structure of eFT508 and ETC-206. Also, some new skeletons were disclosed and showed novel mechanisms, including non-traditional ATP competition and induced protein degradation by proteolysis targeting chimeras. Ongoing preclinical research and clinical trials will provide us more information on these new compounds and MNKs novel functions beyond cancer."

Journal • Review • Genetic Disorders • Obesity • Oncology • Targeted Protein Degradation • EIF4E

Phase Ib pharmacodynamic study of the MNK inhibitor Tomivosertib (eFT508) combined with paclitaxel in patients with refractory metastatic breast cancer. (PubMed, Clin Cancer Res) - "We conclude that tomivosertib effectively inhibits MNK1/2 activity in metastatic breast cancer tissue, and that it can safely be combined with paclitaxel in future phase II studies. We demonstrate feasibility of using proteomic profiles, translatomic profiles, and spatial distribution of immune cell infiltrates for clinical pharmacodynamic studies."

Journal • Metastases • P1 data • PK/PD data • Breast Cancer • Oncology • Solid Tumor • EIF4E

Computational Assessment of Clinical Drugs against SARS-CoV-2: Foreseeing Molecular Mechanisms and Potent Mpro Inhibitors. (PubMed, Chemphyschem) - "Post-MD analyses demonstrate Darunavir, Ponatinib, and Tomivosertib forming a stable complex with Mpro, characterized by less fluctuation of Cα atoms, smooth and stable root-mean-square deviation (RMSD), and robust contact with the active site residues. Overall, the computational assessment earmarks promising candidates from the Excelra database, emphasizing on carrying out exhaustive biochemical experiments along with clinical trials. The work lays the foundation for potential therapeutic interventions in treating COVID-19."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Ketamine Reverses Chronic Corticosterone-Induced Behavioral Deficits and Hippocampal Synaptic Dysfunction by Regulating eIF4E/BDNF Signaling. (PubMed, Neuropharmacology) - "Notably, the eIF4E/MNK1 signaling inhibitor, eFT508, blocked Ketamine's antidepressant effect, leading to a return of depression-like phenotype and impaired synaptic signaling. These findings suggest that Ketamine exerts its antidepressant action through the regulation of the eIF4E/BDNF signaling pathway in the hippocampus. This study provides novel insights into the molecular mechanisms underlying Ketamine's therapeutic effects and highlights the potential of targeting this pathway for future MDD treatment strategies."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • Targeted Protein Degradation • EIF4E

Interleukin-6 induces nascent protein synthesis in human dorsal root ganglion nociceptors primarily via MNK-eIF4E signaling. (PubMed, Neurobiol Pain) - "To pinpoint the specific molecular mechanisms driving this IL-6-driven increase in nascent proteins, we used the specific MNK1/2 inhibitor eFT508...Our findings provide clear evidence that IL-6 drives nascent protein synthesis in human TRPV1+ nociceptors primarily via MNK1/2-eIF4E signaling. The work links animal findings to human nociception, creates a framework for additional hDRG signaling experiments, and substantiates the continued development of MNK inhibitors for pain."

Journal • Pain • EIF4E • IL6 • TRPV1

MNK-driven eIF4E phosphorylation regulates the fibrogenic transformation of mesenchymal cells and chronic lung allograft dysfunction. (PubMed, J Clin Invest) - "Treatment with an MNK1/2 inhibitor (eFT-508) abrogated allograft fibrosis in an orthotopic murine lung-transplant model. Together these studies identify what we believe is a previously unrecognized MNK/eIF4E/ATX/β-catenin signaling pathway of fibrotic transformation of MCs and present the first evidence, to our knowledge, for the utility of MNK inhibitors in fibrosis."

Journal • Fibrosis • Immunology • Respiratory Diseases • Transplantation • EIF4E

Remodelling of the translatome controls diet and its impact on tumorigenesis. (PubMed, Nature) - "Our findings reveal that on a ketogenic diet, treatment with eFT508 (also known as tomivosertib; a P-eIF4E inhibitor) restrains pancreatic tumour growth. Thus, our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • AMPK • EIF4E

Selective and effective suppression of pancreatic cancer through MNK inhibition. (PubMed, Immunopharmacol Immunotoxicol) - " The MNK-eIF4E-β-catenin axis plays a critical role in pancreatic cancer progression and chemoresistance, distinguishing pancreatic cancer cells from normal cells. Targeting MNK kinases with inhibitors like eFT508 presents a promising therapeutic strategy for pancreatic cancer, with potential for selective efficacy and reduced toxicity."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • EIF4E

KICKSTART: Tomivosertib Combined with Pembrolizumab in Previously Untreated PD-L1 High Stage IIIB/IV NSCLC (IASLC-WCLC 2024) - No abstract available

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

Tomivosertib reduces ectopic activity in dorsal root ganglion neurons from patients with radiculopathy. (PubMed, Brain) - "Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain."

Journal • Neuralgia • Pain • EIF4E

ephrin-B2 promotes nociceptive plasticity and hyperalgesic priming through EphB2-MNK-eIF4E signaling in both mice and humans. (PubMed, Pharmacol Res) - "In experiments on human DRG neurons, ephrin-B2 increased eIF4E phosphorylation and enhanced Ca2+ responses to PGE2 treatment, both blocked by eFT508. We conclude that ephrin-B2 acts directly on mouse and human sensory neurons to induce nociceptor plasticity via MNK-eIF4E signaling, offering new insight into how ephrin-B signaling promotes pain."

Journal • Preclinical • Immunology • Osteoarthritis • Pain • Rheumatoid Arthritis • Rheumatology • EIF4E • EPHB2 • MKNK1

An Open-label Study of the Effect of Tomivosertib (eFT508) in Patients With Advanced Castrate-resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=16 | Terminated | Sponsor: Effector Therapeutics | Completed ➔ Terminated; Terminated early due to a lack of efficacy.

Metastases • Trial termination • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

TSC2 loss in neural progenitor cells suppresses translation of ASD/NDD-associated transcripts in an mTORC1- and MNK1/2-reversible fashion. (PubMed, bioRxiv) - "Most notably, numerous non-monogenic ASD-NDD- and epilepsy-associated genes identified in patients harboring putative loss-of-function mutations, including protein truncating, or damaging missense variants, were translationally suppressed in TSC2 -Null NPCs, and their translation were reversed upon RMC-6272 or eFT-508 treatment. Our study here establishes the importance of mTORC1-eIF4F and MNK-eIF4E-mediated mRNA translation in TSC, ASD and other neurodevelopmental disorders and lay the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for TSC as well as ASD/NDD."

Journal • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Oncology • Psychiatry • EIF4E • EIF4G1 • TSC1 • TSC2

PHOSPHO-EIF4E IS REQUIRED FOR NEUTROPHIL EXTRACELLULAR TRAP FORMATION IN A MURINE MODEL OF EXTRANODAL LYMPHOMA. (EHA 2024) - "We report that phosphorylation of eIF4E is required for NET formation. Moreover, our data indicate that NETsare an underappreciated feature of extranodal DLBCLs, and that therapeutically targeting eIF4Ephosphorylation may be an effective strategy to reduce NETosis – and thereby tumour growth – in thisaggressive DLBCL subtype. Figure 1."

Preclinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EIF4E

Novel engineered regulatory macrophages combined with ICIs for post-transplant recurrence after liver transplantation for HCC. (ASCO 2024) - "Tomivosertib downregulated the expression of PD-L1 and attenuated the immunosuppressive effect. Pexidartinib inhibited the polarization of the M2 pathway and upregulated the expression of CD80, CD86, and MHC II, enhancing the ability of antigen presentation... Engineered Mregs combined with ICIs enhances immunotherapeutic efficacy and provides a viable therapeutic approach for posttransplant recurrence after liver transplantation for HCC."

IO biomarker • Post-transplantation • Hepatocellular Cancer • Hepatology • Transplant Rejection • Transplantation • CD80 • CD86

Post-transcriptional Regulation of Autotaxin Involves RNA-binding Protein HuR and Its Intermediate Role in MNK/eIF4E Activation Within Lung-transplanted Mesenchymal Cells (ATS 2024) - "Further investigations utilizing actinomycin D confirmed the regulatory role of HuR in stabilizing ATX mRNA...Analysis of our heavy polysomal fraction, qPCR, and protein data indicated decreased HuR expression following eFT-508 treatment, a specific MNK1/2 inhibitor... Our findings highlight the regulatory role of HuR in ATX expression within LTx MCs, suggesting that targeting HuR could be a promising therapeutic strategy to mitigate the development of CLAD. Additionally, our study underscores the significance of the MNK/eIF4E signaling pathway in modulating HuR alongside fibrotic mediators, including ATX, within the context of lung transplantation."

Fibrosis • Oncology • Respiratory Diseases • Transplantation • EIF4E • ENPP2

Tomivosertib Combined With Pembrolizumab in Subjects With PD-L1 Positive NSCLC (KICKSTART) (clinicaltrials.gov) - P2 | N=68 | Active, not recruiting | Sponsor: Effector Therapeutics | Trial completion date: May 2024 ➔ Dec 2024 | Trial primary completion date: Mar 2024 ➔ Oct 2024

Combination therapy • Trial completion date • Trial primary completion date • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1