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

Jae Hyun Kim, Kilsoo Jung, Chulho Lee, Doona Song, Kibum Kim, Hee Chan Yoo, Seung Joon Park, Jong Soon Kang, Kyeong Ryoon Lee, Sunghoon Kim, Jung Min Han, Gyoonhee Han

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Article number104907
JournalBioorganic Chemistry
Volume112
DOIs
Publication statusPublished - 2021 Jul

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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