약학회지
YAKHAK HOEJI
ISSN 0377-9556 (PRINT)
ISSN 2383-9457 (ONLINE)

Table. 2.

Table. 2.

Small Molecule Glutaminase Inhibitors

Compound Isoform selectivity Binding sites Mode of action Potency Notes
DON3) Non-selective Substrates binding Irreversible, covalent bond at catalytic serine IC50 = 1 µM for KGA Poor selectivity, off-target effect and toxicity

Physapubescin19) KGA Substrates binding, allosteric Reversible, competitive/partial non-competitive(mixed mode) IC50 = 9.89 µM Natural withanolide purified from Physalis pubescens

Thiazolidine-2,4-diones21) KGA Substrates binding, allosteric Reversible, competitive/partial non-competitive(mixed mode) IC50 = 35 nM (for the best derivative) Synergistic in combination with BPTES

Ardisianone22) GAB Allosteric Mixed non-competitive IC50 = 0.28 µM for GAB, 2.1 mM for KGA Ingredients derived from plants of the genus Ardisia; Binding site is located at C terminal of GLS2 monomer, distinct from those of DON, 968, or BPTES

96823) GAC(GLS1) Allosteric Reversible, non-competitive IC50 = 9.3 µM for GAC H-ring significantly affected potency

BPTES25) GLS1 Allosteric Reversible, non-competitive IC50 = 371 nM for GAC, 8.60 µM for KGA Issues in solubility and metabolic stability

CB-83932) GLS1 Allosteric Reversible, non-competitive IC50 = 29 nM for GAC, 24 nM for KGA Currently in clinical trials (Telaglenastat)

Compound 2033) KGA Allosteric Not determined IC50 = 1 nM for KGA Selectively taken up, and accumulated by cancer cells

LL20234) GLS1 Allosteric Non-competitive IC50 = 6 nM for GLS1 Macrocyclic

IPN6009035) GLS1 Allosteric Not determined IC50 = 31 nM for GLS1 Excellent physicochemical and pharmacokinetic properties, Clinical trial terminated and declared not due to any safety or tolerability issues

CPU-L136) GLS1 Allosteric Not determined IC50 = 27 nM for GLS1 More potent with greater solubility than CB-839
Yakhak Hoeji 2021;65:344-8 https://doi.org/10.17480/psk.2021.65.5.344
© 2021 Yakhak Hoeji