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A novel rapamycin analog is highly selective for mTORC1 in vivo

Katherine H Schreiber1, Sebastian I Arriola Apelo2,3,4, Deyang Yu3,4,5

  • 1Buck Institute for Research on Aging, Novato, CA, 94945, USA.

Nature Communications
|July 21, 2019
PubMed

Insights

A new compound, DL001, selectively inhibits mTORC1, a key pathway in aging and disease. This selective inhibition reduces side effects commonly seen with rapamycin, offering a safer therapeutic approach.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Aging Research

Background:

  • Rapamycin inhibits mechanistic Target Of Rapamycin Complex 1 (mTORC1), extending lifespan and treating age-related diseases.
  • Rapamycin's therapeutic potential is limited by off-target inhibition of mTOR complex 2, causing metabolic and immunological side effects.

Purpose of the Study:

  • To identify and characterize DL001, a novel rapamycin analog with enhanced selectivity for mTORC1.
  • To evaluate the efficacy and safety profile of DL001 in preclinical models.

Main Methods:

  • Developed DL001, a FKBP12-dependent rapamycin analog with 40x greater selectivity for mTORC1 over mTORC2 compared to rapamycin.
  • Administered DL001 to cell culture lines and C57BL/6J mice to assess mTORC1 inhibition and side effects.

Main Results:

  • DL001 demonstrated potent mTORC1 inhibition in vitro and in vivo.
  • DL001 treatment in mice preserved glucose homeostasis and showed reduced or no adverse effects on lipid metabolism and the immune system.
  • DL001 repressed elevated mTORC1 activity in cells lacking functional tuberous sclerosis complex, restoring normal gene expression.

Conclusions:

  • Highly selective pharmacological inhibition of mTORC1 is achievable in vivo using DL001.
  • Selective mTORC1 inhibition significantly mitigates the side effects associated with conventional rapalogs, suggesting improved therapeutic potential.

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