2-Substituted Nγ-glutamylanilides as novel probes of ASCT2 with improved potency

Michael L. Schulte; Eric S. Dawson; Sam A. Saleh; Madison L. Cuthbertson; H. Charles Manning

doi:10.1016/j.bmcl.2014.10.098

2-Substituted Nγ-glutamylanilides as novel probes of ASCT2 with improved potency

Michael L. Schulte, Eric S. Dawson, Sam A. Saleh, Madison L. Cuthbertson, H. Charles Manning

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

29 Scopus citations

Abstract

Herein, we report the discovery and structure-activity relationships (SAR) of 2-substituted glutamylanilides as novel probes of the steric environment comprising the amino acid binding domain of alanine-serine-cysteine transporter subtype 2 (ASCT2). Focused library development led to three novel, highly potent ASCT2 inhibitors, with N-(2-(morpholinomethyl)phenyl)-l-glutamine exhibiting the greatest potency in a live-cell glutamine uptake assay. This level of potency represents a three-fold improvement over the most potent, previously reported inhibitor in this series, GPNA. Furthermore, this and other compounds in the series exhibit tractable chemical properties for further development as potential therapeutic leads.

Original language	English (US)
Pages (from-to)	113-116
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2014.10.098
State	Published - Jan 1 2015
Externally published	Yes

Keywords

ASCT2
Cancer
Glutamine
Metabolism
SLC1A5

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2014.10.098

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abstract = "Herein, we report the discovery and structure-activity relationships (SAR) of 2-substituted glutamylanilides as novel probes of the steric environment comprising the amino acid binding domain of alanine-serine-cysteine transporter subtype 2 (ASCT2). Focused library development led to three novel, highly potent ASCT2 inhibitors, with N-(2-(morpholinomethyl)phenyl)-l-glutamine exhibiting the greatest potency in a live-cell glutamine uptake assay. This level of potency represents a three-fold improvement over the most potent, previously reported inhibitor in this series, GPNA. Furthermore, this and other compounds in the series exhibit tractable chemical properties for further development as potential therapeutic leads.",

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AU - Schulte, Michael L.

AU - Dawson, Eric S.

AU - Saleh, Sam A.

AU - Cuthbertson, Madison L.

AU - Manning, H. Charles

PY - 2015/1/1

Y1 - 2015/1/1

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AB - Herein, we report the discovery and structure-activity relationships (SAR) of 2-substituted glutamylanilides as novel probes of the steric environment comprising the amino acid binding domain of alanine-serine-cysteine transporter subtype 2 (ASCT2). Focused library development led to three novel, highly potent ASCT2 inhibitors, with N-(2-(morpholinomethyl)phenyl)-l-glutamine exhibiting the greatest potency in a live-cell glutamine uptake assay. This level of potency represents a three-fold improvement over the most potent, previously reported inhibitor in this series, GPNA. Furthermore, this and other compounds in the series exhibit tractable chemical properties for further development as potential therapeutic leads.

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KW - Glutamine

KW - Metabolism

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2-Substituted Nγ-glutamylanilides as novel probes of ASCT2 with improved potency

Abstract

Keywords

ASJC Scopus subject areas

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