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Discovery of the First Raptor (Regulatory-Associated Protein of mTOR) Inhibitor as a New Type of Antiadipogenic Agent.

Authors :
Yan XL
Pan YH
Fan RZ
Song QQ
Li S
Huang JL
Li W
Huang D
Yuan FY
Tang GH
Rao Y
Huang ZS
Yin S
Source :
Journal of medicinal chemistry [J Med Chem] 2023 Apr 27; Vol. 66 (8), pp. 5839-5858. Date of Electronic Publication: 2023 Apr 04.
Publication Year :
2023

Abstract

Raptor, a regulatory-associated protein of mTOR, has been genetically proved to be an important regulator in lipogenesis. However, its druggable potential is rarely investigated, largely due to the lack of an inhibitor. In this study, the antiadipogenic screening of a daphnane diterpenoid library followed by target fishing led to the identification of a Raptor inhibitor, 1c (5/7/6 carbon ring with orthoester and chlorine functionalities). Pharmacodynamic studies verified that 1c is a potent and tolerable antiadipogenic agent in vitro and in vivo. Mechanistic studies revealed that the targeting of Raptor by 1c could block the formation of mTORC1 and then downregulate the downstream S6K1- and 4E-BP1-mediated C/EBPs/PPARĪ³ signaling, eventually retarding adipocyte cell differentiation at the early stage. These findings suggest that Raptor can be explored as a novel therapeutic target for obesity and its related complications, and 1c as the first Raptor inhibitor may provide a new therapeutic option for these conditions.

Details

Language :
English
ISSN :
1520-4804
Volume :
66
Issue :
8
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
37014798
Full Text :
https://doi.org/10.1021/acs.jmedchem.3c00067