Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1.

Departments of Bioengineering and Therapeutic Sciences and Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, and Graduate Group in Biophysics, University of California, San Francisco, CA 94158.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 03/2013; DOI: 10.1073/pnas.1218165110
Source: PubMed

ABSTRACT The Large-neutral Amino Acid Transporter 1 (LAT-1)-a sodium-independent exchanger of amino acids, thyroid hormones, and prescription drugs-is highly expressed in the blood-brain barrier and various types of cancer. LAT-1 plays an important role in cancer development as well as in mediating drug and nutrient delivery across the blood-brain barrier, making it a key drug target. Here, we identify four LAT-1 ligands, including one chemically novel substrate, by comparative modeling, virtual screening, and experimental validation. These results may rationalize the enhanced brain permeability of two drugs, including the anticancer agent acivicin. Finally, two of our hits inhibited proliferation of a cancer cell line by distinct mechanisms, providing useful chemical tools to characterize the role of LAT-1 in cancer metabolism.



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