TY - JOUR
T1 - Recent Progress in the Discovery of Allosteric Inhibitors of Kidney-Type Glutaminase
AU - Zimmermann, Sarah C.
AU - Duvall, Bridget
AU - Tsukamoto, Takashi
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Kidney-type glutaminase (GLS), the first enzyme in the glutaminolysis pathway, catalyzes the hydrolysis of glutamine to glutamate. GLS was found to be upregulated in many glutamine-dependent cancer cells. Therefore, selective inhibition of GLS has gained substantial interest as a therapeutic approach targeting cancer metabolism. Bis-2-[5-(phenylacetamido)-1,3,4-thiadiazol-2-yl]ethyl sulfide (BPTES), despite its poor physicochemical properties, has served as a key molecular template in subsequent efforts to identify more potent and drug-like allosteric GLS inhibitors. This review article provides an overview of the progress made to date in the development of GLS inhibitors and highlights the remarkable transformation of the unfavorable lead into "druglike" compounds guided by systematic SAR studies.
AB - Kidney-type glutaminase (GLS), the first enzyme in the glutaminolysis pathway, catalyzes the hydrolysis of glutamine to glutamate. GLS was found to be upregulated in many glutamine-dependent cancer cells. Therefore, selective inhibition of GLS has gained substantial interest as a therapeutic approach targeting cancer metabolism. Bis-2-[5-(phenylacetamido)-1,3,4-thiadiazol-2-yl]ethyl sulfide (BPTES), despite its poor physicochemical properties, has served as a key molecular template in subsequent efforts to identify more potent and drug-like allosteric GLS inhibitors. This review article provides an overview of the progress made to date in the development of GLS inhibitors and highlights the remarkable transformation of the unfavorable lead into "druglike" compounds guided by systematic SAR studies.
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U2 - 10.1021/acs.jmedchem.8b00327
DO - 10.1021/acs.jmedchem.8b00327
M3 - Article
C2 - 29969024
AN - SCOPUS:85057520547
SN - 0022-2623
VL - 62
SP - 46
EP - 59
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 1
ER -