The Design and Study of Anticancer Therapeutics Inspired by Natural Substrates of LAT1

PROJECT SUMMARY
Cancer’s uncontrolled cell proliferation is supported in part by the overexpression of the large neutral amino acid
transporter 1 (LAT1). LAT1 is key in meeting the unusually high nutrient demand of cancer cells for natural-
occurring hydrophobic amino acids. The proposed work is significant because current drug treatments suffer
from limitations involving the poor selectivity for cancer cells over healthy cells, inefficient drug-uptake, and
treatment-resistance which often occurs with progression and recurrence of the disease. Furthermore, a major
roadblock in drug development for cancerous tumors is the inability of many small molecules to penetrate into
tumor cells. An effective strategy for addressing these drawbacks involves targeting drugs that are amenable for
uptake via LAT1. The expected outcome in designing structures that can serve as LAT1 substrates is targeted
delivery through enhanced drug selectivity for cancer cells over healthy cells. The overarching goal of this project
is to develop novel 1,2,3-triazole-based amino acid chemotherapeutics as structural analogues of natural LAT1
substrates. 1,2,3-Triazoles are important scaffolds in compounds with a wide range of biological activities,
including anticancer activity. In addition, these units are often attached to other biologically active molecules to
enhance potency. Anticancer drug designs that take advantage of the therapeutic potential of the 1,2,3-triazole
rings in combination with the uptake efficiency that can be achieved via LAT1 are innovative, novel, and wide
open for exploration. The approach to this project will be carried out with two specific aims, (1) the design and
synthesis of the triazole-based amino acid-drug assemblies and (2) in vitro characterization of drug
candidates. In the first aim, we will design three classes of amino acid analogues containing the 1,2,3-triazolyl
rings linked to aromatic (Ar) moieties with known anticancer activity. The core skeletal designs will consist of an
unnatural amino acid backbone, the natural amino acid tyrosine, and meta-tyrosine; the latter two are highly
compatible with LAT1. Biological evaluation of the final triazole amino acid-drug assemblies and their precursors
will be used to decipher the structure-activity relationship for anticancer activity and cellular uptake. The second
aim will focus on the biological studies. These investigations will use cell viability studies to probe the anticancer
properties of the compounds developed in aim 1. The second aim will also probe intracellular delivery;
morphological changes in the cells post drug administration; and signaling pathways and biochemical
parameters the molecules are predicted to target (p53 tumor suppressor gene function and reactive oxygen
species (ROS) production).

Grant Number: 1R15CA277652-01
NIH Institute/Center: NIH
Principal Investigator: Karelle Aiken