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mTORC1 REGULATION

Split-personality inhibitors

Nature Chemical Biology volume 17, pages 1012–1013 (2021)Cite this article

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A rationally designed class of mTORC1 inhibitors combines the selectivity of rapamycin with the potency of mTOR kinase inhibitors.

Rapalogs are the most widely used class of mTOR inhibitors. Like rapamycin (Fig. 1), they employ an unusual allosteric mechanism that involves binding to both mTOR and a second protein called FKBP12. Despite their high affinity and selectivity, rapalogs are surprisingly mild growth suppressors in cancer cells. One reason for this is that mTOR exists in two distinct complexes. Only one of these, mTOR complex 1 (mTORC1), which controls protein synthesis and autophagy, is sensitive to rapamycin (Fig. 1). The other, mTOR complex 2 (mTORC2), which controls cell survival and metabolism partly via the Akt proto-oncogene, is rapamycin resistant. A second reason is that even mTORC1 and some substrates, including the 4E-binding protein (4EBP) translation repressors, are only partially inhibited by rapamycin4,5,6.

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Fig. 1: Bi-steric mTORC1 inhibitors combine the selectivity of rapamycin with the potency of mTORKIs.

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  1. Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA

    Carson C. Thoreen

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  1. Carson C. Thoreen
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Correspondence to Carson C. Thoreen.

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Thoreen, C.C. Split-personality inhibitors. Nat Chem Biol 17, 1012–1013 (2021). https://doi.org/10.1038/s41589-021-00820-8

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