Format

Send to

Choose Destination
ACS Med Chem Lett. 2016 Mar 13;7(5):520-4. doi: 10.1021/acsmedchemlett.6b00060. eCollection 2016 May 12.

Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold.

Author information

1
Johns Hopkins Drug Discovery Program, Johns Hopkins University, Baltimore, Maryland 21205, United States; Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21205, United States.
2
Johns Hopkins Drug Discovery Program, Johns Hopkins University , Baltimore, Maryland 21205, United States.
3
Department of Pathology, Johns Hopkins University , Baltimore, Maryland 21231, United States.
4
Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.

Abstract

A series of allosteric kidney-type glutaminase (GLS) inhibitors were designed and synthesized using 1,4-di(5-amino-1,3,4-thiadiazol-2-yl)butane as a core scaffold. A variety of modified phenylacetyl groups were incorporated into the 5-amino group of the two thiadiazole rings in an attempt to facilitate additional binding interactions with the allosteric binding site of GLS. Among the newly synthesized compounds, 4-hydroxy-N-[5-[4-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]butyl]-1,3,4-thiadiazol-2-yl]-benzeneacetamide, 2m, potently inhibited GLS with an IC50 value of 70 nM, although it did not exhibit time-dependency as seen with CB-839. Antiproliferative effects of 2m on human breast cancer lines will be also presented in comparison with those observed with CB-839.

KEYWORDS:

Glutaminase; allosteric inhibition; cancer metabolism

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center