AG-881 (Pan-IDH Inhibitor)

Proposed Mechanism of Action

AG-881 is an oral inhibitor of mutated isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2). In preclinical studies, AG-881 demonstrated the ability to penetrate the blood-brain barrier. Mutations to IDH1 or IDH2 lead to a loss of normal activity and a gain of a new function, resulting in the production of the oncometabolite 2-hydroxyglutarate (2-HG).1,2 In vitro studies suggest that 2-HG, which is present at elevated levels in patients with IDH mutations, may drive epigenetic changes that block normal cellular differentiation, leading to a cancerous state.2-6

AG-881 by Disease State

AG-881 in Glioma

Rationale for Clinical Development

IDH1 or IDH2 mutations have been found in many types of cancers, including grade II/III glioma and secondary glioblastoma.7-9 The ability of AG-881 to cross the blood-brain barrier and target IDH1 and IDH2 mutations has led to its clinical investigation in malignant glioma.

AG-881 is being developed in collaboration with Agios Pharmaceuticals.

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.


  1. Ward PS, et al. Cancer Cell. 2010;17:225-234. PMID: 20171147
  2. Figueroa ME, et al. Cancer Cell. 2010;18:553-567. PMID: 21130701
  3. Cardaci S, Ciriolo MR. Int J Cell Biol. 2012;2012:161837. PMID: 22888353
  4. Krall AS, Christofk HR. Nature. 2013;496:38-40. PMID: 23552939
  5. Losman JA, et al. Science. 2013;339:1621-1625. PMID: 23393090
  6. Turcan S, et al. Nature. 2012;483:479-483. PMID: 22343889
  7. Cairns RA, Mak TW. Cancer Discov. 2013;3:730-741. PMID: 23796461
  8. Yang H, et al. Clin Cancer Res. 2012;18:5562-5571. PMID: 23071358
  9. Thol F, et al. Haematologica. 2010;95:1668-1674. PMID: 20494930