2. Academic Validation
  3. Novel allosteric glutaminase 1 inhibitors with macrocyclic structure activity relationship analysis

Novel allosteric glutaminase 1 inhibitors with macrocyclic structure activity relationship analysis

  • Bioorg Med Chem Lett. 2022 Nov 1:75:128956. doi: 10.1016/j.bmcl.2022.128956.
Eun Ji Lee 1,  Krishna Babu Duggirala 2,  Yujin Lee 2,  Mi Ran Yun 3,  Jiyoon Jang 4,  Rajath Cyriac 2,  Myoung Eun Jung 5,  Gildon Choi 2,  Chong Hak Chae 5,  Byoung Chul Cho 6,  Kwangho Lee 7
Affiliations

Affiliations

  • 1 Department of Research Support, Yonsei Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea.
  • 2 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Medicinal Chemistry & Pharmacology, University of Science & Technology, Daejeon 34113, South Korea.
  • 3 Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea; Yonsei New Ii Han Institute for Integrative Lung Cancer Research, Yonsei University College of Medicine, Seoul 03722, South Korea.
  • 4 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Chemistry, Sungkyunkwan University, Suwon 16419, South Korea.
  • 5 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
  • 6 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, South Korea. Electronic address: CBC1971@yuhs.ac.
  • 7 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Medicinal Chemistry & Pharmacology, University of Science & Technology, Daejeon 34113, South Korea. Electronic address: kwangho@krict.re.kr.
PMID: 36038117 DOI: 10.1016/j.bmcl.2022.128956
Abstract

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.

Keywords

Anticancer; BPTES; Cancer metabolism; GLS1; Glutaminase 1; KEAP1; KRAS; Macrocycle.

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