Design, Synthesis, and Pharmacological Evaluation of Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl Sulfide 3 (BPTES) Analogs As Glutaminase Inhibitors

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2012 Nov 16

PMID 23151085

Citations 100

Authors

Krupa Shukla

Dana V Ferraris

Ajit G Thomas

Marigo Stathis

Bridget Duvall

Greg Delahanty

Jesse Alt

Rana Rais

Camilo Rojas

Ping Gao

Yan Xiang

Chi V Dang

Barbara S Slusher

Takashi Tsukamoto

Affiliations

Soon will be listed here.

Abstract

Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as a molecular probe to determine the therapeutic potential of GLS inhibition. In an attempt to identify more potent GLS inhibitors with improved drug-like molecular properties, a series of BPTES analogs were synthesized and evaluated. Our structure-activity relationship (SAR) studies revealed that some truncated analogs retained the potency of BPTES, presenting an opportunity to improve its aqueous solubility. One of the analogs, N-(5-{2-[2-(5-amino-[1,3,4]thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl)-2-phenyl-acetamide 6, exhibited similar potency and better solubility relative to BPTES and attenuated the growth of P493 human lymphoma B cells in vitro as well as in a mouse xenograft model.

Citing Articles

Discovery and Optimization of Ergosterol Peroxide Derivatives as Novel Glutaminase 1 Inhibitors for the Treatment of Triple-Negative Breast Cancer.

Luo R, Zhao H, Deng S, Wu J, Wang H, Guo X Molecules. 2024; 29(18).

PMID: 39339370 PMC: 11434480. DOI: 10.3390/molecules29184375.

Metabolic Reprogramming in Glioblastoma Multiforme: A Review of Pathways and Therapeutic Targets.

Cortes Ballen A, Amosu M, Ravinder S, Chan J, Derin E, Slika H Cells. 2024; 13(18.

PMID: 39329757 PMC: 11430559. DOI: 10.3390/cells13181574.

Glutaminolysis is a Potential Therapeutic Target for Kidney Diseases.

Ou L, Liu Y, Qiu S, Yang C, Tang J, Li X Diabetes Metab Syndr Obes. 2024; 17:2789-2807.

PMID: 39072347 PMC: 11283263. DOI: 10.2147/DMSO.S471711.

HIF2α inhibits glutaminase clustering in mitochondria to sustain growth of clear cell Renal Cell Carcinoma.

Zhao W, Kim B, Coffey N, Bowers S, Jiang Y, Bowman C bioRxiv. 2024; .

PMID: 38746132 PMC: 11092754. DOI: 10.1101/2024.05.04.592520.

Exploiting the Achilles' heel of cancer: disrupting glutamine metabolism for effective cancer treatment.

Fan Y, Xue H, Li Z, Huo M, Gao H, Guan X Front Pharmacol. 2024; 15:1345522.

PMID: 38510646 PMC: 10952006. DOI: 10.3389/fphar.2024.1345522.

References

Martin-Rufian M, Tosina M, Campos-Sandoval J, Manzanares E, Lobo C, Segura J . Mammalian glutaminase Gls2 gene encodes two functional alternative transcripts by a surrogate promoter usage mechanism. PLoS One. 2012; 7(6):e38380. PMC: 3367983. DOI: 10.1371/journal.pone.0038380. View

Erickson J, Cerione R . Glutaminase: a hot spot for regulation of cancer cell metabolism?. Oncotarget. 2011; 1(8):734-40. PMC: 3018840. DOI: 10.18632/oncotarget.208. View

Robinson M, McBryant S, Tsukamoto T, Rojas C, Ferraris D, Hamilton S . Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES). Biochem J. 2007; 406(3):407-14. PMC: 2049044. DOI: 10.1042/BJ20070039. View

Le A, Lane A, Hamaker M, Bose S, Gouw A, Barbi J . Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012; 15(1):110-21. PMC: 3345194. DOI: 10.1016/j.cmet.2011.12.009. View

Yuneva M, Fan T, Allen T, Higashi R, Ferraris D, Tsukamoto T . The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 2012; 15(2):157-70. PMC: 3282107. DOI: 10.1016/j.cmet.2011.12.015. View

Zhou L, Yang L, Tilton S, Wang J . Development of a high throughput equilibrium solubility assay using miniaturized shake-flask method in early drug discovery. J Pharm Sci. 2007; 96(11):3052-71. DOI: 10.1002/jps.20913. View

Schuhmacher M, Staege M, Pajic A, POLACK A, Weidle U, Bornkamm G . Control of cell growth by c-Myc in the absence of cell division. Curr Biol. 1999; 9(21):1255-8. DOI: 10.1016/s0960-9822(99)80507-7. View

Seltzer M, Bennett B, Joshi A, Gao P, Thomas A, Ferraris D . Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res. 2010; 70(22):8981-7. PMC: 3058858. DOI: 10.1158/0008-5472.CAN-10-1666. View

Le A, Cooper C, Gouw A, Dinavahi R, Maitra A, Deck L . Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A. 2010; 107(5):2037-42. PMC: 2836706. DOI: 10.1073/pnas.0914433107. View

10.

Curthoys N, Watford M . Regulation of glutaminase activity and glutamine metabolism. Annu Rev Nutr. 1995; 15:133-59. DOI: 10.1146/annurev.nu.15.070195.001025. View

11.

Wang J, Erickson J, Fuji R, Ramachandran S, Gao P, Dinavahi R . Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010; 18(3):207-19. PMC: 3078749. DOI: 10.1016/j.ccr.2010.08.009. View

12.

Kenny J, Bao Y, Hamm B, Taylor L, Toth A, Wagers B . Bacterial expression, purification, and characterization of rat kidney-type mitochondrial glutaminase. Protein Expr Purif. 2003; 31(1):140-8. DOI: 10.1016/s1046-5928(03)00161-x. View

13.

Erdmann N, Zhao J, Lopez A, Herek S, Curthoys N, Hexum T . Glutamate production by HIV-1 infected human macrophage is blocked by the inhibition of glutaminase. J Neurochem. 2007; 102(2):539-49. PMC: 1976281. DOI: 10.1111/j.1471-4159.2007.04594.x. View

14.

Shijie J, Takeuchi H, Yawata I, Harada Y, Sonobe Y, Doi Y . Blockade of glutamate release from microglia attenuates experimental autoimmune encephalomyelitis in mice. Tohoku J Exp Med. 2009; 217(2):87-92. DOI: 10.1620/tjem.217.87. View

15.

Masson J, Darmon M, Conjard A, Chuhma N, Ropert N, Thoby-Brisson M . Mice lacking brain/kidney phosphate-activated glutaminase have impaired glutamatergic synaptic transmission, altered breathing, disorganized goal-directed behavior and die shortly after birth. J Neurosci. 2006; 26(17):4660-71. PMC: 2745954. DOI: 10.1523/JNEUROSCI.4241-05.2006. View

16.

Richards J, Ballard T, Melander C . Inhibition and dispersion of Pseudomonas aeruginosa biofilms with reverse amide 2-aminoimidazole oroidin analogues. Org Biomol Chem. 2008; 6(8):1356-63. DOI: 10.1039/b719082d. View

17.

DeBerardinis R, Sayed N, Ditsworth D, Thompson C . Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008; 18(1):54-61. PMC: 2476215. DOI: 10.1016/j.gde.2008.02.003. View

18.

Bolchi C, Pallavicini M, Bernini S, Chiodini G, Corsini A, Ferri N . Thiazole- and imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase. Bioorg Med Chem Lett. 2011; 21(18):5408-12. DOI: 10.1016/j.bmcl.2011.07.003. View

19.

Shapiro R, Clark V, Curthoys N . Inactivation of rat renal phosphate-dependent glutaminase with 6-diazo-5-oxo-L-norleucine. Evidence for interaction at the glutamine binding site. J Biol Chem. 1979; 254(8):2835-8. View

20.

Katt W, Ramachandran S, Erickson J, Cerione R . Dibenzophenanthridines as inhibitors of glutaminase C and cancer cell proliferation. Mol Cancer Ther. 2012; 11(6):1269-78. PMC: 3620022. DOI: 10.1158/1535-7163.MCT-11-0942. View