A novel rapamycin analog is highly selective for mTORC1 in vivo

Research output: Contribution to journalArticle

Authors

  • Katherine H. Schreiber
  • Sebastian I. Arriola Apelo
  • Deyang Yu
  • Jacqueline A. Brinkman
  • Michael C. Velarde
  • Faizan A. Syed
  • Chen Yu Liao
  • Emma L. Baar
  • Kathryn A. Carbajal
  • Dawn S. Sherman
  • Denise Ortiz
  • Regina Brunauer
  • Shany E. Yang
  • Stelios T. Tzannis
  • Brian K. Kennedy
  • Dudley W. Lamming

External Institution(s)

  • Buck Institute for Age Research
  • University of Wisconsin-Madison
  • Department of Veterans Affairs
  • Aeonian Pharmaceuticals, Inc.
  • University of the Philippines
  • Dominican University of California
  • Texas A&M University

Details

Original languageEnglish (US)
Article number3194
JournalNature communications
Volume10
Issue number1
StatusPublished - Dec 1 2019
Peer-reviewedYes

Abstract

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.

Citation formats

APA

Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., ... Lamming, D. W. (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature communications, 10(1), [3194]. https://doi.org/10.1038/s41467-019-11174-0

Harvard

Schreiber, KH, Arriola Apelo, SI, Yu, D, Brinkman, JA, Velarde, MC, Syed, FA, Liao, CY, Baar, EL, Carbajal, KA, Sherman, DS, Ortiz, D, Brunauer, R, Yang, SE, Tzannis, ST, Kennedy, BK & Lamming, DW 2019, 'A novel rapamycin analog is highly selective for mTORC1 in vivo', Nature communications, vol. 10, no. 1, 3194. https://doi.org/10.1038/s41467-019-11174-0