Amino acids are essential for protein synthesis, they are supporting cell growth, and metabolism. System L belongs to the family of sodium-independent transport proteins. They can carry neutral amino acids across the cell membrane.

System L contains four different transporters, LAT 1-4. LAT1 and 2 are heterodimers that consist of a catalytic light chain (SLC7A5 or SLC7A8, respectively). And it binds to a heavy chain (4F2hc or CD98hc, SLC3A2).  LAT3 and LAT4 belong to the SLC family 43 (SCL43A1 and SCL43A2, respectively).

LAT1 possesses specific tissue distribution, it highly expressed in cells that require a constant supply of amino acids.

Furthermore, LAT1 extensively over-expresses in tumors and metastases. the overexpressed-LAT1 protein associates with unfavorable prognosis in many types of cancer, such as breast, prostate, lung, colorectal, head, and neck cancer as well as in gliomas.

In this article, we will introduce a potent LAT1 inhibitor, KMH-233.

KMH-233, a potent, reversible, and selective l-type amino acid transporter 1 (LAT1) inhibitor. It inhibits the uptake of LAT1 substrate, l-leucine (IC50=18 μM) as well as cell growth. KMH-233 significantly potentiates the efficacy of Bestatin and Cisplatin even at low concentrations (25 μM).

In a competitive inhibition assay with [14C]-L-leucine (LAT1 substrate) and [14C]-L-alanine (LAT2 substrate) in the MCF-7 cells.

KMH-233 inhibits the cellular uptake of [14C]-Lleucine (0.157 µM) significantly in a concentration-dependent manner. It exhibits an IC50 value of 18.2 ± 1.2 µM. Contrarily, KMH-233 is not able to inhibit [14C]-Lalanine (10.0 µM) significantly within the concentration range of 50-1000 µM. Additionally, the exact IC50 value of KMH-233is >1mM.

KMH-233 affects the cell growth of MCF-7 cells. Additionally, it has the ability to potentiate the anti-proliferative effects of the aminopeptidase inhibitor. Over a 72 h incubation, KMH-233 alone exhibits a significant reduction of cell growth with an IC50 value of 124±24 µM). Thus, KMH-233 exhibits only 6.9-times less inhibition of L-leucine uptake than cell growth This proves that inhibition of LAT1 could be the primary mechanism of its antiproliferative efficacy.

In conclusion, KMH-233, as a potent LAT1 inhibitor, has anti-cancer activity in vitro.  


Huttunen KM, et al.  J Med Chem. 2016;59(12):5740-5751.