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

Bridget Duvall; Sarah C Zimmermann; Run-Duo Gao; Ajit G Thomas; Filip Kalčic; Vijayabhaskar Veeravalli; Amira Elgogary; Rana Rais; Camilo Rojas; Anne Le; Barbara S Slusher; Takashi Tsukamoto

doi:10.1016/j.bmc.2020.115698

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. Epub 2020 Aug 6.

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: ttsukamoto@jhmi.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Site / drug effects
Benzene Derivatives / chemical synthesis
Benzene Derivatives / chemistry
Benzene Derivatives / pharmacology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Glutaminase / antagonists & inhibitors*
Glutaminase / metabolism
Humans
Kidney / enzymology*
Molecular Structure
Solubility
Structure-Activity Relationship
Sulfhydryl Compounds / chemical synthesis
Sulfhydryl Compounds / chemistry
Sulfhydryl Compounds / pharmacology*

Substances

Benzene Derivatives
Enzyme Inhibitors
Sulfhydryl Compounds
Glutaminase

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding