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

Michael F. Wempe; Promsuk Jutabha; Vijay Kumar; James A. Fisher; Katie Waers; Meagan D. Holt; Andrew M. Dodson; Julia Bautista; Deshae T. Gehr; Donald S. Backos; Amit Kumar; Peter J. Rice; Naohiko Anzai; Kunio Saito; Koji Oda; Yoshikatsu Kanai; Hitoshi Endou

doi:10.18103/mra.v7i12.2014

DOIdoi.org/10.18103/mra.v7i12.2014

01 · ABSTRACT

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.

↓ Read PDF

02 · PUBLICATION RECORD

Article details

JournalMedical Research Archives

IssueVol 7 No 12 (2019): Vol.7 Issue 12, December, 2019

SectionResearch Articles

Published18 December 2019

DOI10.18103/mra.v7i12.2014

ISSN2375-1924

03 · RIGHTS & REUSE

Rights & reuse

This article is published under a Creative Commons Attribution License (CC BY 3.0) and may be shared or distributed by anyone as long as attribution is given to the journal.

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

Abstract

Article details

Rights & reuse

Authors & affiliations

Michael F. Wempe

Promsuk Jutabha

Vijay Kumar

James A. Fisher

Katie Waers

Meagan D. Holt

Andrew M. Dodson

Julia Bautista

Deshae T. Gehr

Donald S. Backos

Amit Kumar

Peter J. Rice

Naohiko Anzai

Kunio Saito

Koji Oda

Yoshikatsu Kanai

Hitoshi Endou

Submit your own article