Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 24, Pages 11120-11137Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01320
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Funding
- Cancer Research UK [C480/A1141, C5759/A17098, C5759/A20971]
- Bloodwise Clinician Scientist Fellowship [15030]
- Oglesby Leukaemia Clinical Research Fellowship
- Cancer Research UK
- Cancer Research UK [19280, 17098] Funding Source: researchfish
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A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.
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