Poster
33

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

Discussion

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.

Hosted By

ELRIG
The European Laboratory Research & Innovation Group Our Vision : To provide outstanding, leading edge knowledge to the life sciences community on an open access basis
Event Logo Follow us on Twitter

Get the App

Get this event information on your mobile by
going to the appstore or google play and search for 'elrig'
Login
Eventflo Home
copyright ELRIG, eventflo.co.uk, Labhoo Ltd 2003-2021