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Therapeutics

Targeting an oncometabolite

Nature Reviews Cancer volume 13, page 383 (2013)Cite this article

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orally administered AGI-5198 limited the growth of human R132H-IDH1glioma xenografts by 50–60%

Janeta Popovici-Muller and colleagues have developed a selective inhibitor (AGI-5198) of R132H-IDH1, which is the most common mutant of IDH1 in glioma. Along with colleagues from the laboratories of Katharine Yen, Thomas Graeber and Ingo Mellinghoff, they tested the activity of this drug in a patient-derived glioma cell line that has an endogenous R132H-IDH1 mutation. AGI-5198 inhibited, in a dose-dependent manner, the production of (R)-2HG and also limited colony formation in soft agar by up to 60%. By contrast, it had no effect on two patient-derived glioma cell lines with wild-type IDH1. In mice, orally administered AGI-5198 limited the growth of human R132H-IDH1 glioma xenografts by 50–60%. Proliferation rates were reduced in these xenografts, but apoptosis rates were unaffected. Gene expression studies on mRNA isolated from treated xenografts indicated that the transcription of genes involved in the differentiation of oligodendrocytes and astrocytes was increased. This and other analyses indicated that R132H-IDH1 restricts glial differentiation and that this is restored when R132H-IDH1 is inhibited.

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ORIGINAL RESEARCH PAPERS

  1. Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 4 Apr 2013 (doi:10.1126/science.1236062)

    Article  CAS  Google Scholar 

  2. Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 4 Apr 2013 (doi:10.1126/science.1234769)

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  1. Nicola McCarthy
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McCarthy, N. Targeting an oncometabolite. Nat Rev Cancer 13, 383 (2013). https://doi.org/10.1038/nrc3531

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