Allosteric kidney-type glutaminase (GLS) inhibitors with a mercaptoethyl linker |
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| Affiliation: | 1. Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA;2. Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA;3. Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD 21205, USA;4. Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA;1. Center of Drug Discovery, State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, PR China;2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;1. Laboratoire Synthèse et Isolement de Molécules Bioactives (SIMBA, EA 7502), Université de Tours, Faculté de Pharmacie, Parc de Grandmont, 31 Avenue Monge, 37200 Tours, France;2. Department of Chemistry, University of Namur, Rue de Bruxelles 61, 5000 Namur, Belgium;3. Institut de Recherche en Infectiologie de Montpellier (IRIM), CNRS UMR 9004, Université de Montpellier, 34293 Montpellier, France;4. INSERM, IRIM, 34293 Montpellier, France;1. Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa;2. Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France;3. Sorbonne Université, CNRS, FR 2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening facility), Station Biologique de Roscoff, 29680 Roscoff, France;4. Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa;1. Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway, N-9037 Tromsø, Norway;2. The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway, N-9037 Tromsø, Norway;1. College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea;2. Infectious Disease Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea;3. Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea;1. Institute for Clinical Outcomes, Research and Education (ICORE), St Vincent''s University Hospital, Elm Park, Dublin 4, Ireland;2. Department of Physiology, College of Life Sciences, University College Dublin, Dublin, Ireland;3. Department of Surgery, St Vincent''s University Hospital, Elm Park, Dublin 4, Ireland |
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| Abstract: | A series of allosteric kidney-type glutaminase (GLS) inhibitors possessing a mercaptoethyl ( SCH2CH2) linker were synthesized in an effort to further expand the structural diversity of chemotypes derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a prototype allosteric inhibitor of GLS. BPTES analog 3a with a mercaptoethyl linker between the two thiadiazole rings was found to potently inhibit GLS with an IC50 value of 50 nM. Interestingly, the corresponding derivative with an n-propyl (CH2CH2CH2) linker showed substantially lower inhibitory potency (IC50 = 2.3 μM) while the derivative with a dimethylsulfide (CH2SCH2) linker showed no inhibitory activity at concentrations up to 100 μM, underscoring the critical role played by the mercaptoethyl linker in the high affinity binding to the allosteric site of GLS. Additional mercaptoethyl-linked compounds were synthesized and tested as GLS inhibitors to further explore SAR within this scaffold including derivatives possessing a pyridazine as a replacement for one of the two thiadiazole moiety. |
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| Keywords: | Allosteric inhibitor Glutaminase GLS BPTES CB-839 Thioethyl linker |
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