Novel allosteric glutaminase 1 inhibitors with macrocyclic structure activity relationship analysis

Eun Ji Lee, Krishna Babu Duggirala, Yujin Lee, Mi Ran Yun, Jiyoon Jang, Rajath Cyriac, Myoung Eun Jung, Gildon Choi, Chong Hak Chae, Byoung Chul Cho, Kwangho Lee

Research output: Contribution to journalArticlepeer-review


Glutamine-addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co-occurring mutations. Selective glutaminase1 (GLS1) inhibition was reported using BPTES which has novel mode of allosteric inhibition. However, BPTES is a highly hydrophobic and symmetric molecule with very poor solubility which results in suboptimal pharmacokinetic parameters and hinders its further development. As an ongoing effort to identify more drug-like GLS1 inhibitors via systematic structure − activity relationship (SAR) analysis of BPTES analogs, we disclose our novel macrocycles for GLS1 inhibition with conclusive SAR analysis on the core, core linker, and wing linker, respectively. Selected molecules resulted in reduction in intracellular glutamate levels in LR (LDK378-resistant) cells which is consistent to cell viability result. Finally, compounds 13 selectively reduced the growth of A549 and H460 cells which have co-occurring mutations including KRAS and KEAP1.

Original languageEnglish
Article number128956
JournalBioorganic and Medicinal Chemistry Letters
Publication statusPublished - 2022 Nov 1

Bibliographical note

Funding Information:
This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare [HN21C1180], National Research Foundation of Korea grant [No. 2022R1A2C3005817], and Korea Research Institute of Chemical Technology [KK2231-20]. Authors thank Editage ( for English language editing.

Publisher Copyright:
© 2022 The Author(s)

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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