A dual approach for targeting LAT1 in cancer: assay innovation and non-amino acid inhibitor development

The National Institute of General Medical Sciences awarded the Board of Trustees of Southern Illinois University $144,500 on July 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to develop LAT1-selective cancer inhibitors and screening assays.

The research targets L-amino acid transporter 1 (LAT1), which is overexpressed in many cancer cell types but absent in most normal cells. The project aims to create non-amino acid compounds that inhibit LAT1 through a non-competitive mechanism, avoiding the toxic side effects and oral bioavailability limitations of existing amino acid-based inhibitors. Aim 1 encompasses synthesis of amino acid analogs to serve as substrates for developing fluorescence-based assay systems for compound screening and inhibitor potency determinations, along with synthesis of non-amino acid structures based on monoterpene glycoside scaffolds. Aim 2 focuses on establishing stable LAT knockdown and LAT overexpressing cancer cell lines to validate substrate transport activities and screen non-amino compounds for inhibitory action.

The recipient is Southern Illinois University Edwardsville (UEI HQ5NMP5HLL53), located in Edwardsville, Illinois. Performance of work occurs at that location. The period of performance runs from July 1, 2026, through April 30, 2030. This is a Project Grant, the primary assistance type for investigator-initiated research at NIGMS.

Abstract

Amino acids are absorbed and utilized in the body with the help of dedicated transporters that are localized in the cell membranes. In cancer, the malignant cells often require a larger quantity of essential amino acids to survive, proliferate and metastasize thereby causing poor patient outcomes. Among the various transporters, l-amino acid transporter 1 (LAT1) is specifically overexpressed in many cancer cell types to meet the high demand. In contrast, most normal cells do not express LAT1. Clinically, the high expression of LAT1 has been associated with shorter survival in cancer patients. Thus, LAT1 inhibition is sought as a highly promising anti-cancer approach that can selectively target the malignant cells. However, all LAT1 inhibitors developed to date are based on an amino acid structure that results in toxic side effects and limitations relating to oral administration. Our primary goal is to create LAT1 selective inhibitors that have potent anti-cancer activity with fewer unwanted effects. Our design and development efforts will focus on non-amino acid compounds that inhibit LAT1 through a non-competitive mechanism without significant inhibitory effect on LAT2, LAT3, LAT4 or other transporters. In aim 1, we will synthesize amino acid analogs that serve as broad LAT substrates that will be used in the development of new fluorescence-based assay systems for compound screening and inhibitor potency determinations. Concurrently, efforts will be dedicated to synthesizing the non-amino acid structures based on a monoterpene glycoside compound described previously in the literature. Aim 2 is focused on establishing stable LAT knock down and LAT over-expressing cancer cell lines to be used for validating the substrate transport activities and for screening of the non-amino compounds for inhibitory action. The data from this aim will reveal the structure activity relationship of the non-amino acid inhibitors. In aim 3, the inhibitory compounds with the highest LAT1 selectivity will be tested for cellular anti-cancer activity using assays for proliferation, apoptosis, spheroid growth and intracellular signaling alterations.