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  3. Design, synthesis and biological evaluation of symmetric thiadiazole carboxamide derivative as glutaminase inhibitor

Design, synthesis and biological evaluation of symmetric thiadiazole carboxamide derivative as glutaminase inhibitor

  • Bioorg Med Chem Lett. 2026 Feb 21:136:130595. doi: 10.1016/j.bmcl.2026.130595.
Rajath Cyriac 1,  Eun Ji Lee 2,  Yeongju Kwon 3,  Mi Ran Yun 4,  Myoung Eun Jung 5,  Sunjoo Ahn 1,  Chang Hak Chae 6,  Gildon Choi 7,  Byoung Chul Cho 8,  Kwangho Lee 9
Affiliations

Affiliations

  • 1 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Medicinal Chemistry & Pharmacology, Korea National University of Science & Technology, Daejeon 34113, South Korea.
  • 2 Department of Biomedical Science institute, Graduated School of Medical Science, Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, South Korea.
  • 3 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.
  • 4 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.
  • 5 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
  • 6 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea. Electronic address: chchae@krict.re.kr.
  • 7 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Medicinal Chemistry & Pharmacology, Korea National University of Science & Technology, Daejeon 34113, South Korea. Electronic address: gchoi@krict.re.kr.
  • 8 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.
  • 9 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Medicinal Chemistry & Pharmacology, Korea National University of Science & Technology, Daejeon 34113, South Korea. Electronic address: kwangho@krict.re.kr.
PMID: 41730394 DOI: 10.1016/j.bmcl.2026.130595
Abstract

Metabolic reprogramming toward glutamine anaplerosis is a well-established vulnerability in tumors harboring co-occurring KRAS and KEAP1 mutations, creating a dependency on Glutaminase (GLS)-mediated glutaminolysis for survival and growth. Although allosteric GLS inhibitors such as BPTES (Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide) and later-generation analogs such as CB-839 (Telaglenastat) have pharmacologically validated this target, their clinical utility has been constrained by suboptimal drug-like properties, including poor solubility and bioavailability. To overcome these limitations, we developed TRG-192, a novel symmetric amidothiadiazole derivative engineered with a distinct chemical scaffold to enhance physicochemical and pharmacokinetic profiles. In vitro characterization revealed that TRG-192 is a potent GLS inhibitor (IC₅₀ = 68 nM). This biochemical potency translated to a functional effect in a cellular model of glutamine dependence, as evidenced by a significant depletion of intracellular glutamate pools in LDK378-resistant (LR) cells. Furthermore, TRG-192 demonstrated a favorable preclinical safety profile in initial toxicological assessments. Collectively, these data-encompassing potent target engagement, functional on-target activity, and preliminary safety-provide a compelling rationale for the advancement of TRG-192 into in vivo efficacy studies.

Keywords

Anticancer; BPTES; Cancer metabolism; GLS1; Glutaminase 1.

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