Discovery of the First Raptor (Regulatory-Associated Protein of mTOR) Inhibitor as a New Type of Antiadipogenic Agent.
Discovery of the First Raptor (Regulatory-Associated Protein of mTOR) Inhibitor as a New Type of Antiadipogenic Agent.
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DOI：
10.1021/acs.jmedchem.3c00067
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发表时间：
2023-04
影响因子：
7.3
通讯作者：
Xue-long Yan;Yue-Hua Pan;Run-Zhu Fan;Qin-Qin Song-Qin;Shen Li;Jia-Luo Huang;Wei Li;Dong Huang;Fang-yu Yuan;G. Tang;Yong Rao;Zhishu Huang;Sheng Yin
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文献类型：
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作者：
Xue-long Yan;Yue-Hua Pan;Run-Zhu Fan;Qin-Qin Song-Qin;Shen Li;Jia-Luo Huang;Wei Li;Dong Huang;Fang-yu Yuan;G. Tang;Yong Rao;Zhishu Huang;Sheng Yin
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/PPARγ 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.
