title: Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2.
abstract: The glutamine transporter ASCT2 has been identified as a promising target to inhibit rapid growth of cancer cells. However, ASCT2 pharmacology is not well established. In this report, we performed a systematic structure activity analysis of a series of substituted benzylproline derivatives. Substitutions on the phenyl ring resulted in compounds with characteristics of ASCT2 inhibitors. Apparent binding affinity increased with increasing hydrophobicity of the side chain. In contrast, interaction of the ASCT2 binding site with specific positions on the phenyl ring was not observed. The most potent compound inhibits the ASCT2 anion conductance with a Kiof 3μM, which is in the same range as that of more bulky and higher molecular weight inhibitors recently reported by others. The experimental results are consistent with computational analysis based on docking of the inhibitors against an ASCT2 homology model. The benzylproline scaffold provides a valuable tool for further improving binding potency of future ASCT2 inhibitors.
authors.affiliation: Department of Chemistry, Binghamton University, 4400 Vestal Pkwy East, Binghamton, NY 13902, United States.
authors.forename: Kurnvir
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Chemistry, Binghamton University, 4400 Vestal Pkwy East, Binghamton, NY 13902, United States.
authors.forename: Rose
authors.initials: R
authors.lastname: Tanui
authors.affiliation: Department of Chemistry, Binghamton University, 4400 Vestal Pkwy East, Binghamton, NY 13902, United States.
authors.forename: Armanda
authors.initials: A
authors.lastname: Gameiro
authors.affiliation: Department of Chemistry, Binghamton University, 4400 Vestal Pkwy East, Binghamton, NY 13902, United States.
authors.forename: Gilad
authors.initials: G
authors.lastname: Eisenberg
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Claire
authors.initials: C
authors.lastname: Colas
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Avner
authors.initials: A
authors.lastname: Schlessinger
authors.affiliation: Department of Chemistry, Binghamton University, 4400 Vestal Pkwy East, Binghamton, NY 13902, United States. Electronic address: cgrewer@binghamton.edu.
authors.forename: Christof
authors.initials: C
authors.lastname: Grewer
mesh_terms: D026962:Amino Acid Transport System ASC / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D011392:Proline / Q000031:analogs & derivatives* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D026962:Amino Acid Transport System ASC; D011392:Proline
keywords: ASCT2; Glutamine transport; Inhibitors; Kinetics; Neutral amino acid transporter; Patch clamp; Pharmacology