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

Sarah C. Zimmermann; Emily F. Wolf; Andrew Luu; Ajit G. Thomas; Marigo Stathis; Brad Poore; Christopher Nguyen; Anne Le; Camilo Rojas; Barbara S. Slusher; Takashi Tsukamoto

doi:10.1021/acsmedchemlett.6b00060

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

Sarah C. Zimmermann, Emily F. Wolf, Andrew Luu, Ajit G. Thomas, Marigo Stathis, Brad Poore, Christopher Nguyen, Anne Le, Camilo Rojas, Barbara S. Slusher, Takashi Tsukamoto

School of Medicine

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

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.

Original language	English (US)
Pages (from-to)	520-524
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	7
Issue number	5
DOIs	https://doi.org/10.1021/acsmedchemlett.6b00060
State	Published - May 12 2016

Keywords

Glutaminase
allosteric inhibition
cancer metabolism

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.6b00060

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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.",

keywords = "Glutaminase, allosteric inhibition, cancer metabolism",

author = "Zimmermann, {Sarah C.} and Wolf, {Emily F.} and Andrew Luu and Thomas, {Ajit G.} and Marigo Stathis and Brad Poore and Christopher Nguyen and Anne Le and Camilo Rojas and Slusher, {Barbara S.} and Takashi Tsukamoto",

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doi = "10.1021/acsmedchemlett.6b00060",

language = "English (US)",

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AU - Zimmermann, Sarah C.

AU - Wolf, Emily F.

AU - Luu, Andrew

AU - Thomas, Ajit G.

AU - Stathis, Marigo

AU - Poore, Brad

AU - Nguyen, Christopher

AU - Le, Anne

AU - Rojas, Camilo

AU - Slusher, Barbara S.

AU - Tsukamoto, Takashi

PY - 2016/5/12

Y1 - 2016/5/12

N2 - 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.

AB - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

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