A novel rapamycin analog is highly selective for mTORC1 in vivo

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 and Dudley W. Lamming ()
Additional contact information
Katherine H. Schreiber: Buck Institute for Research on Aging
Sebastian I. Arriola Apelo: University of Wisconsin-Madison
Deyang Yu: University of Wisconsin-Madison
Jacqueline A. Brinkman: University of Wisconsin-Madison
Michael C. Velarde: Aeonian Pharmaceuticals, Inc.
Faizan A. Syed: University of Wisconsin-Madison
Chen-Yu Liao: Buck Institute for Research on Aging
Emma L. Baar: University of Wisconsin-Madison
Kathryn A. Carbajal: University of Wisconsin-Madison
Dawn S. Sherman: University of Wisconsin-Madison
Denise Ortiz: Buck Institute for Research on Aging
Regina Brunauer: Buck Institute for Research on Aging
Shany E. Yang: University of Wisconsin-Madison
Stelios T. Tzannis: Aeonian Pharmaceuticals, Inc.
Brian K. Kennedy: Buck Institute for Research on Aging
Dudley W. Lamming: University of Wisconsin-Madison

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11174-0

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