A novel rapamycin analog is highly selective for mTORC1 in vivo

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

doi:10.1038/s41467-019-11174-0

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.

Highlights

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1, extends lifespan and shows strong potential for the treatment of age-related diseases
We determined that DL001 is an effective mTORC1specific rapalog both in cell culture and in vivo, and we demonstrate for the first time that the negative side effects of rapamycin and its analogs, including metabolic disruption and immunosuppression, may be avoided in whole or in part by a compound that targets mechanistic Target Of Rapamycin Complex 1 (mTORC1)
As DL001 is an FKBP12-dependent rapalog, its effects on the rapamycin-resistant functions of mTORC162 is minimal; work in genetic mouse models suggests that inhibition of the rapamycinresistant functions of mTORC1 may be associated with side effects such as allergic asthma, hypoglycemia, seizures, and the ability to build muscle mass with exercise[63,64,65,66]

Summary

Introduction

An inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. Treatment with rapamycin and its analogs (rapalogs) is associated with negative side effects that limit their potential utility as anti-aging therapies These side effects include immunosuppression, glucose intolerance, an increased risk of type 2 diabetes, and disruption of lipid homeostasis[13,14,15,16,17,18,19]. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that such a compound minimizes the negative metabolic and immunological impacts associated with rapamycin and other conventional rapalogs

Methods

Results

Conclusion