tomivosertib (eFT508) / eFFECTOR Therap, SJP Biotec - LARVOL DELTA

Tomivosertib in Relapsed or Refractory Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - P1 | N=8 | Terminated | Sponsor: Northwestern University | N=15 ➔ 8 | Active, not recruiting ➔ Terminated; Premature withdrawal of investigational product per study sponsor.

Enrollment change • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • EIF4E

Live cell imaging reveals paclitaxel-induced lysosome motility and function disruption in DRG neurons. (PubMed, bioRxiv) - "Lysosomal trafficking and homeostasis are biological functions that are pivotal for DRG neurons, given their metabolic demands and extremely long axons. To establish translation relevance, we further show that PTX elevates phosphorylated eiF4E (p-eIF4E) in human DRG neurons, and concurrent eFT508 administration attenuates this effect. Collectively, these findings indicated that PTX disrupts lysosome trafficking and biogenesis, and that MNK inhibition with eFT508 restores lysosomal signaling and can serve as a neuroprotective strategy for CIPN."

Journal • Oncology • Pain • Peripheral Neuropathic Pain • EIF4E • LAMP1 • SQSTM1 • TFEB

Multi-targeted MNK inhibitors as anticancer agents for AML (AACR 2026) - "The compounds show single-digit micromolar inhibition of AML cells expressing mutant FLT3 (MV-411) and are equipotent to tomivosertib, a clinically investigated MNK inhibitor that was included as a standard for comparison. The design, synthesis, and anticancer effects of multi-targeted MNK inhibitors will be described."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AURKA • AURKB • EIF4E • FLT3

Development of the pyridopyrimidine derivative KC12 as a selective dual Pim/Mnk inhibitor to inhibit leukemia cell growth (AACR 2026) - "KC12 exhibits increased aqueous solubility and superior anti-proliferative activity compared to 21o, as well as to the Pim inhibitor TP-3654 and the Mnk inhibitor eFT508. Moreover, KC12 demonstrated a more favorable pharmacokinetic profile than 21o and exhibited enhanced antitumor efficacy in MOLM-13 xenograft models. These findings suggest that KC12 acts as a novel, potent, and selective dual Pim/Mnk inhibitor and is worthy of further development as a therapeutic agent."

Hematological Malignancies • Leukemia • Oncology • EIF4E • EIF4EBP1 • MCL1 • MYC • PIM1

Targeting RNA-binding proteins eIF4E and HuR in lung mesenchymal cells suppresses ATX–LPA–Th2 axis in airway remodeling in chronic allergic asthma (IMMUNOLOGY 2026) - "eIF4E and HuR act at opposite ends of mRNA: eIF4E promoting translation at the 5′ cap and HuR stabilizing transcripts at the 3′ UTR. Targeting these pathways reduce ATX–LPA–Th2 signaling and fibrotic mediator expression in human lung MCs, supporting their potential as complementary therapeutic approaches in airway remodeling in allergic asthma."

Asthma • Fibrosis • Immunology • Inflammation • Respiratory Diseases • CD4 • COL1A1 • CSF2 • EIF4E • ELAVL1 • ENPP2 • IL13 • IL4 • IL5 • IL6

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

Developing dual FLT3/MNK inhibitors to overcome sorafenib resistance in FLT3-ITD AML cells (AACR 2024) - "MNK inhibitor eFT508 could overcome sorafenib resistance. H104 and H118 decreased the levels of p-eIF4E, c-myc and Mcl-1, the downstream substrates of FLT3-ITD and MNK. Our data indicate that the activated MNK is one mechanism of FLT3-ITD resistance and the dual MNK/FLT3 inhibitors have advantage for FLT3-ITD AML treatment."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • EIF4E • FLT3 • MCL1 • MYC • PIM1

The MNK inhibitor EB1 sensitizes AR-V7 positive castration-resistant prostate cancer to enzalutamide (AACR 2024) - "Here we demonstrate that the novel MNK inhibitor EB1 shows promising in vitro results, which cannot be obtained with Type-I MNK inhibitors. The combination of EB1 with the standard of care Enzalutamide provide a novel therapeutic opportunity for the treatment of CRPC, particularly in AR-V7 positive patients."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • EIF4E

Low concentrations of amyloid-beta oligomers induce synaptogenesis characteristic for mild cognitive impairment and alter the de novo proteome. (PubMed, Transl Psychiatry) - "While total de novo protein synthesis remained unchanged under Aβo exposure using bioorthogonal non-canonical amino acid tagging (BONCAT), subsequent proteomic profiling identified selective changes in de novo protein synthesis that are involved in synaptic function, cytoskeletal regulation, mitochondrial activity, autophagy, and the ubiquitin-proteasome system, and part of these dysregulations could be inhibited by eFT508. These findings indicate that Aβo exposure in an in vitro model of AD leads to synaptogenesis and dysregulation in de novo protein synthesis and they identify eFT508 as a compound that can counteract some of these Aβo-induced dysfunctions."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Targeted Protein Degradation

Mechanistic link between eIF4E phosphorylation and viral pathogenesis: Therapeutic insights from a porcine model. (PubMed, Vet Microbiol) - "Furthermore, hypophosphorylation of eIF4E effectively restored antioxidant defenses by regulating the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) induced by arecoline treatment. These findings suggest that inhibitors targeting the MNK1/2-eIF4E axis confer tissue homeostasis and protection through coordinated anti-inflammatory and antioxidant effects. This work not only elucidates a druggable host factor in virus pathogenesis but also provides preclinical evidence for repurposing eFT508-class compounds in antiviral therapy and livestock resilience enhancement."

Journal • Preclinical • Infectious Disease • CAT • EIF4E • IL6 • NLRP3 • TNFA • TNFAIP3

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

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