A small molecule inhibitor of Rheb selectively targets mTORC1 signaling

Sarah J Mahoney,Lisa Molz,Eddine Saiah,Seong A Kang,Sridhar Narayan,George P Vlasuk,Lauren A Berstler

doi:10.1038/s41467-018-03035-z

Abstract

The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling. NR1 potently inhibits mTORC1 driven phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1) but does not inhibit phosphorylation of AKT or ERK. In contrast to rapamycin, NR1 does not cause inhibition of mTORC2 upon prolonged treatment. Furthermore, NR1 potently and selectively inhibits mTORC1 in mouse kidney and muscle in vivo. The data presented herein suggest that pharmacological inhibition of Rheb is an effective approach for selective inhibition of mTORC1 with therapeutic potential.

Highlights

The small G-protein Ras homolog enriched in brain (Rheb) activates the mechanistic target of rapamycin complex 1 in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders
Growth factor signaling into mTORC1 is regulated by the heterotrimeric tuberous sclerosis (TSC) complex, which acts as a GTPase-activating protein (GAP) for Ras homolog enriched in brain (Rheb), a GTP-binding protein that is broadly expressed in human and mammalian tissues[20]
No structural information is available on other components of the mTOR pathway implicated in interactions with Rheb such as the TSC complex

Summary

Introduction

The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. While rapamycin/rapalogs are selective inhibitors of mTORC1 following acute treatment, it has been proposed that the downregulation of mTORC2 activity upon chronic treatment may be the basis for at least some of these adverse clinical effects including insulin resistance[14,15]. In support of this hypothesis, direct mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2 show a similar adverse effect profile[16,17,18,19]. Point mutations in the switch II region of Rheb (Y67A/I69A and I76A/D77A) impair its ability to activate mTORC123, implying that the switch II region is key to Rheb’s function in mTORC1 activation

Methods

Results

Conclusion