Targeting Mutant IDH in Solid and Hematologic Cancers with AG-881: A Potent Brain Penetrant Inhibitor

AG-881 is a potent, orally administered inhibitor that targets the mutant forms of isocitrate dehydrogenase enzymes 1 and 2 (mIDH1 and mIDH2), which are implicated in cancer. Its mechanism of action is to hinder the mIDH's gain-of-function activity, thereby reducing the oncogenic metabolite D-2-hydroxyglutarate (2-HG) and promoting tumor cell differentiation.

In vitro studies have shown that AG-881 has strong inhibitory effects on various mIDH enzymes with low nanomolar potency. It exhibits rapid equilibrium inhibition for certain mIDH1 and mIDH2 homodimers and slow-binding inhibition for others. The compound has also demonstrated efficacy in inhibiting 2-HG production in cell lines and primary patient samples, with IC50 values ranging from 0.04 to 130 nM depending on the mutation type.

Pharmacokinetic studies in mice and rats indicate rapid absorption and low plasma clearance. AG-881 has been tested in mouse xenograft models, where it significantly reduced 2-HG levels in tumors with doses of 30 mg/kg or more. In an orthotopic glioma model, doses of 0.1 mg/kg or more were effective in reducing brain tumor 2-HG levels. The compound also displays excellent brain penetration with favorable brain-to-plasma ratios.

Preclinical safety profiles are supportive of clinical trials, and AG-881 is currently undergoing phase 1 clinical development for patients with advanced solid tumors, including gliomas, and advanced hematologic malignancies. The drug is being evaluated in clinical trials registered at ClinicalTrials.gov with identifiers NCT02481154 and NCT02492737.

The research was presented by Katharine Yen et al. at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in 2017 and published in the journal Molecular Cancer Therapeutics.