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Zimmermann SC, Wolf EF, Luu A, et al. Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold. ACS Med Chem Lett. 2016;7(5):520-4doi: 10.1021/acsmedchemlett.6b00060.
Zimmermann, S. C., Wolf, E. F., Luu, A., Thomas, A. G., Stathis, M., Poore, B., Nguyen, C., Le, A., Rojas, C., Slusher, B. S., & Tsukamoto, T. (2016). Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold. ACS medicinal chemistry letters, 7(5), 520-4. https://doi.org/10.1021/acsmedchemlett.6b00060
Zimmermann, Sarah C, et al. "Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold." ACS medicinal chemistry letters vol. 7,5 (2016): 520-4. doi: https://doi.org/10.1021/acsmedchemlett.6b00060
Zimmermann SC, Wolf EF, Luu A, Thomas AG, Stathis M, Poore B, Nguyen C, Le A, Rojas C, Slusher BS, Tsukamoto T. Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold. ACS Med Chem Lett. 2016 Mar 13;7(5):520-4. doi: 10.1021/acsmedchemlett.6b00060. eCollection 2016 May 12. PMID: 27200176; PMCID: PMC4868099.
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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.

ACS medicinal chemistry letters

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

Affiliations

  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.

PMID: 27200176 PMCID: PMC4868099 DOI: 10.1021/acsmedchemlett.6b00060

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

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