title: Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold.
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.
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, Baltimore, Maryland 21205, United States; Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21205, United States.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Zimmermann
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors.forename: Emily F
authors.initials: EF
authors.lastname: Wolf
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Luu
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors.forename: Ajit G
authors.initials: AG
authors.lastname: Thomas
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors.forename: Marigo
authors.initials: M
authors.lastname: Stathis
authors.affiliation: Department of Pathology, Johns Hopkins University , Baltimore, Maryland 21231, United States.
authors.forename: Brad
authors.initials: B
authors.lastname: Poore
authors.affiliation: Department of Pathology, Johns Hopkins University , Baltimore, Maryland 21231, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Department of Pathology, Johns Hopkins University , Baltimore, Maryland 21231, United States.
authors.forename: Anne
authors.initials: A
authors.lastname: Le
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, Baltimore, Maryland 21205, United States; Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21205, United States.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, Baltimore, Maryland 21205, United States; Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21205, United States.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
keywords: Glutaminase; allosteric inhibition; cancer metabolism