Structure-based modification of pyrazolone derivatives to inhibit mTORC1 by targeting the leucyl-tRNA synthetase-RagD interaction

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Title
Structure-based modification of pyrazolone derivatives to inhibit mTORC1 by targeting the leucyl-tRNA synthetase-RagD interaction
Author(s)
J H Kim; K Jung; C Lee; D Song; K Kim; H C Yoo; S J Park; Jong Soon KangKyeong-Ryoon Lee; S Kim; J M Han; G Han
Bibliographic Citation
Bioorganic Chemistry, vol. 112, pp. 104907-104907
Publication Year
2021
Abstract
The enzyme leucyl-tRNA synthetase (LRS) and the amino acid leucine regulate the mechanistic target of rapamycin (mTOR) signaling pathway. Leucine-dependent mTORC1 activation depends on GTPase activating protein events mediated by LRS. In a prior study, compound BC-LI-0186 was discovered and shown to interfere with the mTORC1 signaling pathway by inhibiting the LRS-RagD interaction. However, BC-LI-0186 exhibited poor solubility and was metabolized by human liver microsomes. In this study, in silico physicochemical properties and metabolite analysis of BC-LI-0186 are used to investigate the addition of functional groups to improve solubility and microsomal stability. In vitro experiments demonstrated that 7b and 8a had improved chemical properties while still maintaining inhibitory activity against mTORC1. The results suggest a new strategy for the discovery of novel drug candidates and the treatment of diverse mTORC1-related diseases.
Keyword
mTORC1Leucyl-tRNA synthetase (LRS)RagDProtein-protein interactionPyrazolone
ISSN
0045-2068
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.bioorg.2021.104907
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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