2. Academic Validation
  3. Allosteric kidney-type glutaminase (GLS) inhibitors with a mercaptoethyl linker

Allosteric kidney-type glutaminase (GLS) inhibitors with a mercaptoethyl linker

  • Bioorg Med Chem. 2020 Oct 15;28(20):115698. doi: 10.1016/j.bmc.2020.115698.
Bridget Duvall 1,  Sarah C Zimmermann 2,  Run-Duo Gao 1,  Ajit G Thomas 1,  Filip Kalčic 1,  Vijayabhaskar Veeravalli 2,  Amira Elgogary 3,  Rana Rais 2,  Camilo Rojas 4,  Anne Le 3,  Barbara S Slusher 2,  Takashi Tsukamoto 5
Affiliations

Affiliations

  • 1 Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 2 Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 3 Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 4 Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 5 Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: [email protected].
PMID: 33069080 DOI: 10.1016/j.bmc.2020.115698
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.

Keywords

Allosteric inhibitor; BPTES; CB-839; GLS; Glutaminase; Thioethyl linker.

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