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

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1 Citation (Scopus)


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
Publication statusPublished - 2021 Jul

Bibliographical note

Funding Information:
This research was supported by a grant from the Translational Research Center for Protein Function Control (Grant NRF-2009-0083522), the Ministry of Science, ICT and Future Planning (Grant NRF-2013M3A6A4072536), the Bio & Medical Technology Development Program of the National Research Foundation (NRF) & funded by the Korean government (MSIP&MOHW) (Grant NRF-2016M3A9B5941215), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI14C1324), KRIBB Research Initiative Program, the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2016R1A6A3A11934092, NRF-2016R1A6A3A11932977 and NRF-2020R1I1A1A01075325), the Graduate School of YONSEI University Research Scholarship Grants in 2017.

Publisher Copyright:
© 2021 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry


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