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Home  >  Medical Research Archives  >  Issue 149  > Developing selective L-Amino Acid Transport 1 (LAT1) inhibitors: A Structure-Activity Relationship overview
Published in the Medical Research Archives
Dec 2019 Issue

Developing selective L-Amino Acid Transport 1 (LAT1) inhibitors: A Structure-Activity Relationship overview

Published on Dec 18, 2019

DOI 

Abstract

 

System L amino acid transporters are a member of the Solute Carrier transporter Family (SLC). L-Amino acid transporter 1 (LAT1) belong to SLC7 and requires the heavy chained 4F2hc chaperone protein for amino acid transport. LAT1 is expressed in tumor cells and cancerous cells in vivo are strongly linked to LAT1 expression. Herein, we provide historical aspects regarding initial Structure Activity Relationship (SAR) findings reported in 2002 with the oocyte model and in 2008 with S2-LAT1 and S2-LAT2 cell lines.  We summarize a series of dichloro- dibromo- and diiodo- tyrosine analogs that were prepared, and tested their potential to inhibit leucine transport in vitro to afford IC50 values with a few being low microM LAT1 inhibitors.  We then summarize our efforts regarding novel LAT1 inhibitors with sub-nanomolar (nM) IC50s to produce JPH203 which has completed Phase I clinical trial and is currently in Phase II trial in Japan. We describe differences observed between LAT1 and LAT2.  Overall, we provide an expanded SAR model regarding potent and selective LAT1 inhibitors.

Author info

Michael Wempe, Promsuk Jutabha, Vijay Kumar, James Fisher, Katie Waers, Meagan Holt, Andrew Dodson, Julia Bautista, Deshae Gehr, Donald Backos, Amit Kumar, Peter Rice, Naohiko Anzai, Kunio Saito, Koji Oda, Yoshikatsu Kanai, Hitoshi Endou

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