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Comment
. 2013 May 13;23(5):570-2.
doi: 10.1016/j.ccr.2013.04.024.

Releasing the block: setting differentiation free with mutant IDH inhibitors

Christopher J Pirozzi  1 , Zachary J Reitman, Hai Yan
Affiliations
Comment

Releasing the block: setting differentiation free with mutant IDH inhibitors

Christopher J Pirozzi et al. Cancer Cell. .

Abstract

Hotspot mutations in IDH1 and IDH2 cause a differentiation block that can promote tumorigenesis. Two recent papers reported that small molecules targeting mutant IDH1 or mutant IDH2 release this differentiation block and/or impede tumor growth, providing a proof-of-concept that mutant IDHs are therapeutically targetable and that their effects are reversible.

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Figures

Figure 1
Figure 1. Small molecule inhibitor AGI-6780 binds to mutant IDH2 and releases a block to differentiation
IDH mutations induce a block to normal differentiation programs leading to accumulation of progenitor cells, as shown in the Waddington differentiation diagram on the left. AGI-6780, shown in green, binds allosterically at the mutant IDH2 homodimer interface and holds the enzyme in the catalytically inactive open conformation (middle). Each member of the IDH2 homodimer pair is shown in purple and teal, respectively, with the R140Q mutation in yellow. Inhibition of mutant IDH2 releases the block and induces differentiation (right).
See this image and copyright information in PMC

Comment on

  • An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.
    Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E, Kunii K, Pedraza A, Schalm S, Silverman L, Miller A, Wang F, Yang H, Chen Y, Kernytsky A, Rosenblum MK, Liu W, Biller SA, Su SM, Brennan CW, Chan TA, Graeber TG, Yen KE, Mellinghoff IK. Rohle D, et al. Science. 2013 May 3;340(6132):626-30. doi: 10.1126/science.1236062. Epub 2013 Apr 4. Science. 2013. PMID: 23558169 Free PMC article.
  • Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.
    Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C, Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, Dorsch M, Agresta S, Schenkein DP, Biller SA, Su SM, de Botton S, Yen KE. Wang F, et al. Science. 2013 May 3;340(6132):622-6. doi: 10.1126/science.1234769. Epub 2013 Apr 4. Science. 2013. PMID: 23558173

References

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