2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Schulte, Michael L.^1,2,3  Khodadadi, Alexandra B.^1,2  Cuthbertson, Madison L.⁴  Smith, Jarrod A.^5,6  Manning, H. Charles^{1,2,3,7,8,9,10} 

[1] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Mol Probes, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, VUIIS, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Med Ctr, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA

[4] Metropolitan Nashville Publ Sch, Hume Fogg Acad High Sch, Nashville, TN 37203 USA

[5] Vanderbilt Univ, Vanderbilt Ctr Struct Biol, Nashville, TN 37232 USA

[6] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA

[7] Vanderbilt Univ, Med Ctr, VICC, Nashville, TN 37232 USA

[8] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37232 USA

[9] Vanderbilt Univ, Med Ctr, Dept Neurosurg, Nashville, TN 37232 USA

[10] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

关键词: ASCT2;    SLC1A5;    Glutamine;    Cancer;    Metabolism;   

DOI  :  10.1016/j.bmcl.2015.12.031

来源: Elsevier

【 摘 要 】

Herein, we report the discovery of 2-amino-4-bis(aryloxybenzyl) aminobutanoic acids as novel inhibitors of ASCT2(SLC1A5)-mediated glutamine accumulation in mammalian cells. Focused library development led to two novel ASCT2 inhibitors that exhibit significantly improved potency compared with prior art in C6 (rat) and HEK293 (human) cells. The potency of leads reported here represents a 40-fold improvement over our most potent, previously reported inhibitor and represents, to our knowledge, the most potent pharmacological inhibitors of ASCT2-mediated glutamine accumulation in live cells. These and other compounds in this novel series exhibit tractable chemical properties for further development as potential therapeutic leads. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

Free