Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Oct 1;29(19):126632.
doi: 10.1016/j.bmcl.2019.126632. Epub 2019 Aug 20.

GAC inhibitors with a 4-hydroxypiperidine spacer: Requirements for potency

Lee McDermott  1 , David Koes  2 , Shabber Mohammed  3 , Prema Iyer  3 , Melissa Boby  3 , Venkatakrishnan Balasubramanian  4 , Mackenzie Geedy  3 , William Katt  5 , Richard Cerione  6
Affiliations

GAC inhibitors with a 4-hydroxypiperidine spacer: Requirements for potency

Lee McDermott et al. Bioorg Med Chem Lett. .

Abstract

Allosteric inhibitors of glutaminase (GAC), such as BPTES, CB-839 and UPGL00019, have great promise as inhibitors of cancer cell growth, but potent inhibitors with drug-like qualities have been difficult to achieve. Here, a small library of GAC inhibitors based on the UPGL00019 core is described. This set of derivatives was designed to assess if one or both of the phenylacetyl groups flanking the UPGL00019 core can be replaced by smaller simple aliphatic acyl groups without loss in potency. We found that one of the phenylacetyl moieties can be replaced by a set of small aliphatic moieties without loss in potency. We also found that enzymatic potency co-varies with the VDW volume or the maximum projection area of the groups used as replacements of the phenylacetyl moiety and used literature X-ray data to provide an explanation for this finding.

Keywords: BPTES; CB-839; GAC; Novel glutaminase inhibitors; UPGL00019; UPGL00019 derivatives.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
BPTES, CB-839 and 4-hydroxypiperidine-containing analogs UPGL00019 and UPGL00020
Figure 2.
Figure 2.
Overlay of 3UO9 (green) and 3VOZ (cyan) (A), 3UO9 and 5I94 (clay) (B) X-rays. Heat map of b-factors for BPTES and UPGL00019
Figure 3.
Figure 3.
Correlation of pIC50 with the cumulative values of VDW volume or MPA of the acyl-R1 and acyl-R2 groups of UPGL000019 and its derivatives.
Figure 4.
Figure 4.
Overlay of 5I94 (brown), 3VP2 (magenta), 3VP3 (blue), and 3VP4 (green) x-ray structures.
Scheme 1.
Scheme 1.
Synthesis of UPGL00019 derivatives. Reagents and conditions: a) NaH, CS2, MeI, THF, rt; b) NH2NH2 MeOH, rt; c) BrCN, Et3N, MeOH, rt; d) R1/R2-acyl chloride or R1/R2-acyl anhydride, Et3N, DMF, rt; e) R1/R2-acid HATU, Et3N, DMF, rt; f) 4N HCl in Dioxane, rt; g) 2-bromo-4-aminothiadiazole, K2CO3, DMSO, 50–55 °C or 2-bromo-4-aminothiadiazole, Et3N, EtOH, 80 °C.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Elgadi KM; Meguid RA; Qian M; Souba WW; Abcouwer SF, Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific alternative splicing. Physiol Genomics 1999, 1 (2), 51–62. - PubMed
    1. Szeliga M; Obara-Michlewska M, Glutamine in neoplastic cells: focus on the expression and roles of glutaminases. Neurochem Int 2009, 55 (1–3), 71–5. - PubMed
    1. Perez-Gomez C; Campos-Sandoval JA; Alonso FJ; Segura JA; Manzanares E; Ruiz-Sanchez P; Gonzalez ME; Marquez J; Mates JM, Co-expression of glutaminase K and L isoenzymes in human tumour cells. Biochem J 2005, 386 (Pt 3), 535–42. - PMC - PubMed
    1. Huang F; Zhang Q; Ma H; Lv Q; Zhang T, Expression of glutaminase is upregulated in colorectal cancer and of clinical significance. Int J Clin Exp Pathol 2014, 7 (3), 1093–100. - PMC - PubMed
    1. Pan T; Gao L; Wu G; Shen G; Xie S; Wen H; Yang J; Zhou Y; Tu Z; Qian W, Elevated expression of glutaminase confers glucose utilization via glutaminolysis in prostate cancer. Biochem Biophys Res Commun 2015, 456 (1), 452–8. - PubMed

Publication types

MeSH terms

LinkOut - more resources