Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma

Abstract

Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma.

MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma

“…Our studies used two orally available small molecule inhibitors which are currently in clinical trials 9 . AG-120 is a potent first-in-class IDH1mut inhibitor 48 , while AG-881 is a potent first-in-class, brain penetrant inhibitor of both IDH1mut and IDH2mut 49 . We investigated their intracellular metabolic effects on two genetically engineered IDH1mut-expressing cell lines using 1 H-, 13 C-, and hyperpolarized 13 C-MRS 35 , 38 , 39 , 47 and observed that some, but unexpectedly not all, of our previously identified IDH1mut-associated intracellular metabolic alterations were reversed with treatment.…”

ABCC8 mRNA expression is an independent prognostic factor for glioma and can predict chemosensitivity

“…World Health Organization (WHO) grade 4 glioblastoma is the most malignant form of glioma with a 5-year relative survival rate of 5% 2 . In recent years, studies have elucidated some genetic changes in glioma, such as IDH1/2 3 , TP53 4 and ATRX 5 mutations, TERT promoter mutations 6 , MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, MET amplification 7 , MGMT promoter methylation 8 , and 1p/19q co-deletion 9 , which have been helpful in guiding the classification and treatment of glioma. As per the WHO’s classification of central nervous system tumors in 2016, for the first time, diffuse gliomas were classified according to IDH1 or IDH2 mutations and the co-deletion of 1p and 19q chromosome arms 10 .…”

“…2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China. 3 Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing 100070, China. 4 China National Clinical Research Center for Neurological Diseases, Beijing 100070, China.…”

Isocitrate Dehydrogenase Mutations in Glioma: Genetics, Biochemistry, and Clinical Indications

“…With the promising findings regarding AGI-5198, second-generation mutant IDH inhibitors are under development and are undergoing evaluation in clinical studies. For example, ivosidenib (AG-120) and vorasidenib (AG-881) have been tested in AML and glioma with IDH mutations [115][116][117][118]. In a recent phase I clinical study with ivosidenib in IDH1-mutated advanced glioma conducted by Mellinghoff et al [119], the mutant IDH inhibitor appeared to be well-tolerated throughout the experiment, which paved the way for subsequent clinical studies to evaluate its therapeutic efficacy.…”

“…Specific small molecular inhibitors of mutant IDH have been developed to inhibit the IDH mutant neomorphic activity [109]. Although several studies have reported some limitations to their application [23,142,143], mutant IDH inhibitors have still shown promising therapeutic benefits in numerous preclinical and clinical studies [116,144,145]. The recent development of glioma mouse models has provided generous insights regarding glioma biology and therapeutics [146].…”