CR-1-31-B / McGill University - LARVOL DELTA

mRNA Translation Inhibition Targets Bioenergetic Homeostasis in AML Cells in Vitro and In Vivo and Synergizes with Cytarabine and Venetoclax (ASH 2023) - "Using the MOLM-14 human AML cell line to model therapy-resistant disease, we previously demonstrated the anti-leukemic effect of a potent and specific eIF4A inhibitor (eIF4Ai), CR-1-31-B, both in vitro and in vivo (Fooks et al, J Exp Clin Cancer Res 2022). This is of interest as several translation inhibitors are currently tested in phase 1/2 clinical trials in solid malignancies. # co-corresponding authors"

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2 • BCL2L1 • CCND3 • CDK4 • EIF4A1 • EIF4A2 • EIF4E • EIF4G1 • IDH1 • MCL1

The novel eIF4A inhibitor synergizes potently with the XPO-1 inhibitor in T-cell lymphoma (AACR 2025) - "We hypothesized that the combination of eIF4A inhibitor (CR-1-31-B) and XPO-1 inhibitor (Selinexor) would exhibit synergistic anti-lymphoma activity in TCL and have potential clinical applications. The combination of eIF4A inhibitor and XPO-1 inhibitor demonstrates potent anti-lymphoma activity in T-cell lymphoma. This novel combination represents a promising therapeutic strategy for patients with TCL, warranting further preclinical investigations and potential clinical translation."

B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • EIF4A1 • EIF4A2

Amidino-Rocaglates (ADRs), a class of synthetic rocaglates, are potent inhibitors of SARS-CoV-2 replication through inhibition of viral protein synthesis. (PubMed, Antiviral Res) - "Previously, the rocaglate natural product silvestrol and synthetic rocaglates such as CR-1-31b were shown to have antiviral effects by inhibiting eukaryotic translation initiation factor 4A1 (eIF4A) function and virus protein synthesis...Mechanistically, cells with mutations of eIF4A1, which are known to reduce rocaglate interaction displayed reduced ADR-associated loss of cellular function, consistent with targeting of protein synthesis. Overall, ADRs and derivatives may offer new potential treatments for SARS-CoV-2 with the goal of developing a broad-acting anti-coronavirus agent."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • EIF4A1 • EIF4A2

Pharmacologic inhibition of eIF4A blocks NRF2 synthesis to prevent osteosarcoma metastasis. (PubMed, Clin Cancer Res) - "Collectively, our data reveal that pharmacologic targeting of eIF4A1 is highly effective in blocking OS metastasis by blunting the NRF2 antioxidant response."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • EIF4A1 • EIF4A2

The novel eIF4A inhibitor potently synergizes with BCL2 inhibitor in high grade B-cell lymphoma with MYC and BCL2 rearrangements through regulating UPR (AACR 2024) - "We tested the anti-lymphoma effect of CR-1-31-B, in combination with Venetoclax in lymphoma cell lines using flow cytometry. These combination is promising and novel treatment for high-grade B-cell lymphoma with MYC and BCL2 rearrangements. Further pre-clinical investigations of this combination for these patients are needed."

IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL6 • EIF4A1 • EIF4A2 • MYC

Novel targets for BRAFV600E and BRAFV600ERAC1P29S drug resistant melanoma (AACR 2024) - "Rac1 P29S -transfected and PLX4720 resistant cell lines had an increase in the Mek/Erk signaling pathway...Drugs that target different subunits of the eIF4F complex (CR-1-31-B, Ribavirin and Briciclib) also decrease BRAFV600E/RAC1P29S and the DR melanoma cell lines growth specifically...When tested in a syngraft model, CR-1-31-B and rapamycin reduced tumor size when using YUMM1.7, YUMM1.7- RAC1P29S and YUMM1.7 RAC1P29S-DR cell lines. Next, we sought to investigate the effect of inhibiting mTOR and eiF4F in the PD-1/PD-L1 axis in tumor cells and tumor associated dendritic cells and macrophages, and how targeting these modifies the tumor microenvironment."

IO biomarker • Melanoma • Oncology • Solid Tumor • BRD4 • CDK9 • EIF4A1 • EIF4E • EIF4G1 • MYC • RAC1 • SMAD3

The novel eIF4A inhibitor potently synergizes with BCL2 inhibitor in high grade B-cell lymphoma with MYC and BCL2 rearrangements through inhibition of UPR (ICKSH 2024) - "If eIF4A inhibitor preferentially inhibit the translation of on- cogenes such as cMyc and venetoclax inhibit the BCL2 in DHL, then the combination of eIF4A inhibitor and BCL2 inhibitor will be highly effective for DHL and potentially safe for animals and humans Method : We tested the anti-lymphoma effect of CR-1-31-B, in com- bination with Venetoclax in lymphoma cell lines using flow cytome- try. Conclusion : These findings suggest that the combination of eIF4A inhibitor and BCL2 inhibitor have potent pharmacological activity in DHL lines, it was closely related with UPR. These combination is promising and novel treatment for high-grade B-cell lymphoma with MYC and BCL2 rearrangements."

Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL6 • EIF4A1 • EIF4A2 • MYC

THE EIF4A1/2 INHIBITOR CR-1-31B DOWN-MODULATES THE ANTIOXIDANT RESPONSE AND INHIBITS LUNG METASTASIS IN OSTEOSARCOMA (CTOS 2023) - No abstract available

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • EIF4A1

Rapamycin-Induced Feedback Activation of eIF4E-EIF4A Dependent mRNA Translation in Pancreatic Cancer. (PubMed, Cancers (Basel)) - "In short, we establish the specific effect of mTOR-S6 on translation in cells lacking 4EBP1 and show that mTOR inhibition leads to feedback activation of translation via AKT-RSK1-eIF4E signals. Therefore, targeting translation downstream of mTOR presents a more efficient therapeutic strategy in pancreatic cancer."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • EIF4A1 • EIF4E • EIF4EBP1

EIF4A inhibition targets bioenergetic homeostasis in AML MOLM-14 cells in vitro and in vivo and synergizes with cytarabine and venetoclax. (PubMed, J Exp Clin Cancer Res) - "We discovered that chemoresistant MOLM-14 cells rely on eIF4A-dependent cap translation for survival in vitro and in vivo. EIF4A drives an intrinsic metabolic program sustaining bioenergetic and redox homeostasis and regulates the expression of anti-apoptotic proteins. Overall, our work suggests that eIF4A-dependent cap translation contributes to adaptive processes involved in resistance to relevant therapeutic agents in AML."

IO biomarker • Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • EIF4A1 • MCL1

A Pan-Cancer Analysis Reveals CLEC5A as a Biomarker for Cancer Immunity and Prognosis. (PubMed, Front Immunol) - "The drug sensitivity analysis screens out potential therapeutic agents associated with CLEC5A expression, including FR-180204, Tivozanib, OSI-930, Linifanib, AC220, VNLG/124, Bexarotene, omacetaxine mepesuccinate, narciclasine, leptomycin B, PHA-793887, LRRK2-IN-1, and CR-1-31B. CLEC5A overexpresses in multiple cancers in contrast to normal tissues, and high CLEC5A expression predicts poor prognosis of patients and immune infiltration. CLEC5A is a potential prognostic biomarker of diverse cancers and a target for anti-tumor therapy."

Biomarker • Journal • Pan tumor • Immune Modulation • Immunology • Infectious Disease • Inflammation • Oncology • CAFs • MSI • TMB

Rocaglates as Antivirals: Comparing the Effects on Viral Resistance, Anti-Coronaviral Activity, RNA-Clamping on eIF4A and Immune Cell Toxicity. (PubMed, Viruses) - "In detail, zotatifin showed reduced RNA-clamping efficiency and antiviral activity compared to silvestrol and CR-1-31-B, but was less cytotoxic for immune cells. Our results underline the potential of rocaglates as broad-spectrum antivirals with no indications for the emergence of escape mutations in HCoV-229E."

Journal • Infectious Disease • Novel Coronavirus Disease • EIF4A1

NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy. (PubMed, Cancers (Basel)) - "We find that a synthetic silvestrol analogue (CR-1-31 B) has nanomolar activity across many cancer cell lines...Accordingly, loss of FN3K results in NRF2 hyper-glycation and inactivation and resensitizes cancer cells to eIF4A inhibition. Together, our findings implicate NRF2 in the translation of eIF4A-dependent mRNAs and point to FN3K inhibition as a new strategy to block NRF2 functions in cancer."

Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • EIF4A1 • KEAP1 • MYC

Eukaryotic Translation Initiation Factor 4AI: A Potential Novel Target in Neuroblastoma. (PubMed, Cells) - "Additionally, this study reveals that CR-1-31-B is effective against NB cell lines at low nanomolar doses (≤20 nM), which have been shown to not affect non-malignant cells in previous studies. Thus, our study provides information of the expression status on eIF4AI in NB and offers initial promising insight into targeting translation initiation as an anti-tumorigenic approach for NB."

Journal • Immunology • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • EIF4A1 • EIF4E • EIF4G1

Targeting eIF4A using rocaglate CR‑1‑31B sensitizes gallbladder cancer cells to TRAIL‑mediated apoptosis through the translational downregulation of c‑FLIP. (PubMed, Oncol Rep) - "Taken together, the results of the present study show that CR‑31 treatment countered the resistance to TRAIL in GBC cells in vitro and in vivo. Therefore, eIF4A may serve as a novel therapeutic target and its combination with TRAIL‑CR‑31 as a therapy may serve as a novel strategy for GBC treatment."

Journal • Gallbladder Cancer • Gastrointestinal Cancer • Hepatology • Solid Tumor • CFLAR • EIF4A1 • TNFA

Intercepted Retro-Nazarov Reaction: Syntheses of Amidino-Rocaglate Derivatives and Their Biological Evaluation as eIF4A Inhibitors. (PubMed, J Am Chem Soc) - "Trapping of the oxyallyl cation with a diverse range of nucleophiles has been used to generate over fifty novel amidino-rocaglate (ADR) and amino-rocaglate derivatives. Subsequently, these derivatives were evaluated for their ability to inhibit cap-dependent protein synthesis where they were found to outperform previous lead compounds including the rocaglate hydroxamate CR-1-31-B."

Journal • Oncology