IDH305

Using both clinical samples and experimental models, we demonstrate that the cell-permeable derivative dimethyl-α-ketoglutarate (DM-α-KG) exacerbates lipopolysaccharide (LPS)-induced tissue injury and cell death, whereas isocitrate dehydrogenase (IDH1) inhibition (IDH-305) or genetic ablation reduces α-KG levels and confers protection...These findings establish α-KG as a critical immunometabolic checkpoint in sepsis that licenses inflammatory cell death via TET2-mediated epigenetic control of AIM2. Our work not only elucidates a novel α-KG/TET2/AIM2 signaling axis in sepsis pathogenesis but also highlights the therapeutic potential of targeting this pathway to modulate immune responses.

P1, N=166, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Feb 2026 --> Feb 2027

P1, N=166, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2025 --> Feb 2026

P1, N=166, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2024 --> Oct 2025

However, current targeted inhibitors of IDH1 mutation (AG120 and IDH305) reversed these effects caused by IDH1 mutation. The in vivo experiment showed that IDH1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to erastin-induced ferroptosis. This study indicated that IDH1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to erastin-induced ferroptosis.

Due to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared.