PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett
Glutaminase GLS1 Inhibitors as Potential Cancer Treatment Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:
1,3,4-Thiadiazole Compounds and Their Use in Treating Cancer
Patent Application Number: WO 2015/181539 A1
Publication date:
3 December 2015
Priority date:
30 May 2014
Priority Application:
GB 1409624.2
Inventors:
Finlay, M. R. V.; Ekwuru, C. T.; Charles, M. D.; Raubo, P. A.; Winter, J. J. G.; Nissink, J. W. M.
Assignee Company:
Astrazeneca AB; SE-151 85 Siidertalje (SE)
Disease Area:
Cancer Research Technology Limited; Angel Building, 407 St. John Street, London, Greater London EC1 V 4AD (GB) Cancer Biological Target: Glutaminase 1 (GLS1)
Summary:
The invention in this patent application relates to 1,3,4-thiadiazole derivatives represented generally by formula (I). These compounds possess activities as inhibitors of the glutaminase 1 enzyme (GLS1) and may be useful in the treatment or prevention of GLS1 mediated disease such as cancer. Glutamine (S-2-amino-4-cabamoylbutanoic acid) is the amide derivative of glutamic acid. It is the most abundant nonessential free amino acid in the plasma, and it is involved in many growth promoting pathways. It plays a significant role in the oxidation process of the tricarboxylic acid (TCA) cycle (a.k.a. citric acid or Krebs cycle), and it participates in nucleotide and amino acid biosynthesis as a nitrogen donor. In 1927, Otto Warburg observed a higher rate of glucose uptake by cancer cells compared to normal cells. During this abnormal activity, the glycolytic pyruvate is converted to lactic acid rather than generating Acetyl CoA. Warburg hypothesized that this metabolic change causes cancer; however, recent studies have shown that this metabolic change is only an outcome of oncogenic mutations of glucose uptake and not the cause. Studies have also shown that many cancer cells are dependent on glutamine metabolism for energy production to meet the demands of their accelerated growth and proliferation. This dependency causes these cancer cells to be sensitive to changes in exogenous glutamine levels. Evidence suggests that the catabolism of glutamine (glutaminolysis) plays a key role in certain cancer types, and it is associated with known oncogenic drivers such as Myc. Glutaminase is an amidohydrolase that catalyzes the first step in the glutaminolysis of glutamine to glutamate. It exists as two isoforms, glutaminase 1 (GLS1) and glutaminase 2 (GLS2), originally identified as the kidney and liver glutaminases, respectively. GLS1 is more ubiquitously expressed than GLS2, and it has two splice variants, the kidney-type glutaminase (KGA) isoform and the glutaminase C isoform (GAC), both of which are located in the mitochondria. GLS1 expression is associated with tumor growth and malignancy in a number of disease types. Thus, inhibitors of GLS1 such as the compounds described in this patent application are potentially useful for the treatment of different forms of cancer, either as monotherapy or in combination with other anticancer agents.
Important Compound Classes:
Received:
r XXXX American Chemical Society
A
January 12, 2016
dx.doi.org/10.1021/acsmedchemlett.6b00016 | ACS Med. Chem. Lett. XXXX, XXX, 000–000
ACS Medicinal Chemistry Letters Key Structures:
PATENT HIGHLIGHT
The inventors described the structures of 35 examples of formula (I) as well as many of their stereo isomers including the following representative examples:
Biological Assay: (a) GLS Enzyme Potency Assay (b) GLS Cell Potency Assay (c) GLS Cell Proliferation Assay (d) Mouse Xenograft Model Biological Data:
Recent Review Articles:
The following biological testing data were obtained from the above representative examples of formula (I) compounds:
1. Lukey, M. J.; Wilson, K. F.; Cerione, R. A. Future Med. Chem. 2013, 5 (14), 1685 1700. 2. Lu, W.-Q.; Pelicano, H.; Huang, P. Cancer Cell 2010, 18 (3), 199 200. 3. Wise, D. R.; Thompson, C. B. Trends Biochem. Sci. 2010, 35 (8), 427 433.
’ AUTHOR INFORMATION Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
B
dx.doi.org/10.1021/acsmedchemlett.6b00016 |ACS Med. Chem. Lett. XXXX, XXX, 000–000
