A collaborative hit-finding approach to identify novel inhibitors of mutant isocitrate dehydrogenase


As part of AstraZeneca (AZ)’s Open Innovation initiative, the Cancer Research UK Manchester Institute (CRUK-MI) and AZ entered into a collaboration to screen a new drug target against AZ’s compound collection. The collaboration allowed staff from the CRUK-MI Drug Discovery Unit unprecedented access to AZ’s high throughput screening (HTS) facilities and compound collection. A HTS of approximately 1.35 million compounds was undertaken against the R123H mutant form of isocitrate dehydrogenase 1 (IDH1 R132H) in order to identify novel hit matter. This mutation leads to a loss of the normal enzymatic activity of IDH1 and the acquisition of a neomorphic activity resulting in reduction of -ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG). Such gain of function mutations in IDH1 and IDH2 are found in up to 70% of low grade and secondary glioma cases and up to 10% of acute myeloid leukemia cases and, as such, this enzyme is an attractive anti-cancer target.
Hits identified in the HTS using a biochemical NADPH fluorescence assay were re-confirmed using Rapid Fire mass spectrometry via quantification of 2-HG production, resulting in an initial overall hit rate of 2.1 %. Those compounds with potential liabilities related to an undesirable mechanism of action were removed using potency “ratio” testing and performing the assay in the presence and absence of detergent. A secondary orthogonal assay surface plasmon resonance (SPR) was used to confirm binding of scaffolds of interest to the target protein. This cascade identified a number of potential series of which 3 series have been selected for further prosecution at CRUK-MI. The results of this collaboration and the output will be discussed.

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