SBI-756 / TGen, National Cancer Institute - Bethesda, Sanford-Burnham Medical Research Institute - LARVOL DELTA

Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer. (PubMed, Neoplasia) - "In vivo, inhibition of EIF4G1 by the inhibitor, SBI-0640756, attenuated HnRNP l-induced tumor progression and immunosuppressive activity. And most of all, therapeutic synergy between HnRNP L knockdown and Anti-PD-1 could significantly suppress xenograft prostate cancer growth. In summary, this study revealled the molecular mechanism of HnRNP L regulating the immune infiltration, which provides a new theoretical basis for overcoming the limitation of immunotherapy for CRPC."

Checkpoint inhibition • Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD4 • CD8 • CXCL8 • EIF4G1 • MYC

Targeting eIF4G1-dependent translation in melanoma. (PubMed, bioRxiv) - "We previously identified SBI-756, a small molecule that interferes with the eIF4F assembly and overcomes melanoma resistance to BRAF inhibitors...Alone, M19-6 reduced melanoma growth and metastasis in a xenograft model. M19-6 offers a new therapeutic modality to overcome resistance and metastasis."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hepatology • Lymphoma • Melanoma • Non-Hodgkin’s Lymphoma • Oncology • Pancreatic Cancer • Solid Tumor • EIF4E • EIF4G1

Coupled inhibition of transcription and translation as potential therapeutic approach for dedifferentiated liposarcoma (ECP 2024) - "The study illustrates the notable therapeutic efficacy of A1874 and SBI-0640756, both individually and in combination, against DDLPS. Notably, the combined treatment showcases superior effectiveness, indicating synergistic interactions. This synergy is likely attributed to the modulation of critical oncogenic pathways, resulting in enhanced tumour growth suppression compared to monotherapy."

Liposarcoma • Oncology • Sarcoma • Solid Tumor • BRD4 • EIF4G1

Targeting the translation initiation complex component eIF4G1 in melanoma (AACR 2024) - "Leveraging our findings with the small molecule SBI-756, which interacts with eIF4G1 and impairs eIF4F complex assembly, we set to map domains that are required for SBI-756 activity...Among those, autophagy inhibitors synergized with our lead compound, M19-6, resulting in efficient melanoma cell death, using notably lower concentrations of these inhibitors. Our findings identify the eIF4G1 MA3 domain as an important player in eIF4F assembly and a potential target for cancer therapy."

Melanoma • Oncology • Solid Tumor • EIF4A1 • EIF4A2 • EIF4E • EIF4G1

Targeting a Highly Deregulated eIF4F Translation Initiation Complex Sensitises IM‑Resistant Cells to Tyrosine Kinase Inhibitors and Effectively Suppresses BCR-ABL1 Protein Expression (ASH 2022) - "Methods A high content antibody microarray was performed in BCR-ABL1+ cells co-transduced with wild-type (WT) AHI-1 or the deletion of AHI-1 SH3 domain (SH3Δ) with or without imatinib (IM)...Most interestingly, SBI-756 treatment reduced protein expression of BCR-ABL1 (70%) and cyclin D3 (40%) in these cells. Conclusion We have uncovered that the eIF4F complex, the key regulator of the mRNA-ribosome recruitment phase of translation initiation, has increased activity in IM-resistant cells. eIF4G1 inhibitor treatment sensitises IM-resistant cells to TKI and reduces BCR-ABL1 protein expression, providing potential treatment strategies to overcome TKI resistance."

Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR • CCND3 • CD34 • EIF4E • EIF4G1

Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition. (PubMed, Sci Rep) - "SBI-756, a small molecule inhibitor of eIF4F assembly, sensitizes human Ph+ and Ph-like B-ALL cells to dasatinib cytotoxicity without affecting survival of T lymphocytes or natural killer cells. These findings support the further evaluation of eIF4F-targeted molecules in combination therapies with TKIs in B-ALL and other blood cancers."

Journal • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • EIF4E • EIF4G1

[VIRTUAL] Omics guided small molecule inhibitor screen for the identification of therapeutic vulnerabilities in metastatic lung adenocarcinoma. (ASCO 2021) - "Interestingly, small molecules targeting EIF4G1 (SBI-0640756), ribosome biogenesis/RNA export (YM155), and rRNA synthesis (CX5461) were effective in inducing cell death while inhibitors blocking mTOR signaling, EIF2A phosphorylation, and EIF4F complex assembly were not . Our data demonstrates that MYBL2-driven metastatic disease is uniquely sensitive to inhibitors of the protein translation machinery . Importantly, these inhibitors significantly outperform current standard-of-care agents cisplatin and pemetrexed . To our knowledge, our study is the first to demonstrate that blocking EIF4G1 effectively induces widespread cell death in metastatic lung adenocarcinoma models ."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EIF2A • EIF4E • EIF4G1 • MYBL2

Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax. (PubMed, Br J Cancer) - "Our data highlight a novel combination for treatment of aggressive lymphomas, and establishes its efficacy and selectivity using preclinical models."

Journal • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EIF4E • EIF4G1