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Allosteric kidney-type glutaminase (GLS) inhibitors with a mercaptoethyl linker.
Duvall, Bridget; Zimmermann, Sarah C; Gao, Run-Duo; Thomas, Ajit G; Kalcic, Filip; Veeravalli, Vijayabhaskar; Elgogary, Amira; Rais, Rana; Rojas, Camilo; Le, Anne; Slusher, Barbara S; Tsukamoto, Takashi.
Afiliación
  • Duvall B; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Zimmermann SC; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Gao RD; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Thomas AG; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Kalcic F; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Veeravalli V; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Elgogary A; Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Rais R; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Rojas C; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Le A; Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Slusher BS; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Tsukamoto T; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: ttsukamoto@jhmi.edu.
Bioorg Med Chem ; 28(20): 115698, 2020 10 15.
Article en En | MEDLINE | ID: mdl-33069080
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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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Compuestos de Sulfhidrilo / Derivados del Benceno / Inhibidores Enzimáticos / Glutaminasa / Riñón Límite: Humans Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Compuestos de Sulfhidrilo / Derivados del Benceno / Inhibidores Enzimáticos / Glutaminasa / Riñón Límite: Humans Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos