ERG 245 / Ergon Pharma - LARVOL DELTA

BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma. (PubMed, Cell Rep Med) - "We evaluate the potency of a BCAT1 inhibitor, ERG245, as a single or combination treatment with tyrosine kinase inhibitor (TKI) in vivo...Our results indicate that BCAT1 benefits HCC growth through HIF-1α-induced metabolic reprogramming. Targeting BCAT1 will provide an effective therapeutic strategy for HCC patients."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • BCAT1 • HIF1A

BCAT1 promotes HCC metabolic reprogramming and survival through HIF-1α stabilization (AACR 2024) - "ERG245 also profoundly inhibited HCC growth in vitro and in vivo together with Sorafenib, a tyrosine kinase inhibitor (TKI) used in HCC by increasing the apoptotic cell death. Our findings unequivocally demonstratethat BCAT1 confers a growth advantage to HCC cells by stabilizing HIF-1α and orchestrating HIF-1α-mediated metabolic reprogramming. Consequently, targeting BCAT1 emerges as a promising therapeutic strategy for HCC patients."

Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • BCAT1 • HIF1A

BRANCHED CHAIN AMINO ACID TRANSAMINASE 1 ASSOCIATES WITH THE KU70/KU86 HETERODIMER AND MODULATES THE DNA DAMAGE RESPONSE IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA CELLS (EHA 2022) - "Drug combination experiments using the DNA damaging agent (etoposide) and a specific BCAT inhibitor (ERG245) were performed in vitro and in vivo in PDX T-ALL models. BCAT1 is involved in sustaining genomic integrity following DNA damage through its interaction with the Ku70/Ku86 heterodimer, known to mediate classical non-homologous end-joining. Our results identify BCAT1 as a novel therapeutic target and suggest that the combination between DNA double stand break inducing agents (such as etoposide) and a BCAT inhibitor could be particularly useful in NOTCH1-mutant T-ALL cases."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • BCAT1 • NOTCH1 • TLX1

Temporal inhibition of BCAT1 alters metal homeostasis leading to reversal of terminal exhaustion of CD8 T cells, increased cytotoxicity, and increased efficacy of checkpoint inhibition in cancer (AACR 2022) - "We have previously demonstrated that BCAT1, the enzyme responsible for the reversible transamination of leucine in the cytosol, is a druggable target in immune-oncology: the small molecule inhibitor ERG245 dramatically increases the efficacy of anti-PD-1 treatment in the moderately immunogenic CT26 colon cancer model...Withdrawal of BCAT1 restored or reversed the cell phenotype leading to epigenetically altered CD8+ T cells with decreased histone acetyltransferase and histone demethylase presence, increased cytotoxicity, and increased ribosome biogenesis. Collectively, the data suggest that temporal inhibition of BCAT1 inhibition induces profound effects on CD8+ T cells including increased cytotoxicity and suppression of terminal exhaustion, thus rendering the cells rescuable by anti-PD-1 therapy."

Checkpoint inhibition • Clinical • IO biomarker • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BCAT1 • CD4 • CD8 • CXCL13 • GZMB • HAVCR2 • TGFB1

[VIRTUAL] BCAT1 as a druggable target in immuno-oncology (AACR-I 2020) - "Withdrawal of ERG245 restored intracellular lactate levels without reversing the metabolic reprogramming of the cells. We propose that these are elements of a mechanism that links temporal inhibition of BCAT1 to the rise of highly energetic CD8+ T cells with increased cytotoxicity and proliferative capacity in vitro and in vivo."

IO Biomarker • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • BCAT1 (Branched Chain Amino Acid Transaminase 1 ) • CD8 • IFNG