Targeting Mutant IDH1 with BAY 1436032: A Promising Therapeutic Approach for Cancer

The study introduces BAY 1436032, a newly developed inhibitor specifically targeting the mutant form of isocitrate dehydrogenase 1 (mIDH1), which is often found in various types of cancer. This enzyme, when mutated, leads to the production of the oncometabolite 2-hydroxyglutarate (2-HG), which is implicated in cancer progression by disrupting cellular differentiation and causing hypermethylation of histones and DNA.

The research details the optimization process that identified BAY 1436032 as a candidate for treating mIDH1-dependent cancers. The inhibitor demonstrated high selectivity and potency against multiple IDH1-R132X mutant variants in vitro, effectively reducing 2-HG levels in both patient-derived and engineered cell lines. The compound also induced differentiation and maturation in mIDH1 tumor cells at nanomolar concentrations.

Furthermore, the study highlights the in vivo efficacy of BAY 1436032 in glioma and intrahepatic cholangiocarcinoma tumor models, with a focus on 2-HG levels as a potential biomarker. The compound's ability to penetrate the blood-brain barrier was supported by preclinical data.

The conclusion of the research underscores the potential of BAY 1436032 as a potent and selective inhibitor of mIDH1, with a Phase I clinical trial being planned to evaluate its safety, pharmacokinetics, and anti-tumor effects in solid tumor patients. The findings were presented at the 107th Annual Meeting of the American Association for Cancer Research, with the abstract published in the Cancer Research journal.