Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 12, Pages 5740-5751Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00190
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Funding
- Academy of Finland [256837]
- Sigrid Juselius Foundation
- Emil Aaltonen Foundation
- Orion Research Foundation
- Academy of Finland (AKA) [256837, 256837] Funding Source: Academy of Finland (AKA)
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The L-type amino acid transporter 1 (LAT1) is a transmembrane protein carrying bulky and neutral amino acids into cells. LAT1 is overexpressed in several types of tumors, and its inhibition can result in reduced cancer cell growth. However, known LAT1 inhibitors lack selectivity over other transporters. In the present study, we designed and synthesized a novel selective LAT1 inhibitor (1), which inhibited the uptake of LAT1 substrate, L-leucin as well as cell growth. It also significantly potentiated the efficacy of bestatin and cisplatin even at low concentrations (25 mu M). Inhibition was slowly reversible, as the inhibitor was able to be detached from the cell surface and blood-brain barrier. Moreover, the inhibitor was metabolically stable and selective toward LAT1. Since the inhibitor was readily accumulated into the prostate after intraperitoneal injection to the healthy mice, this compound may be a promising agent or adjuvant especially for the treatment of prostate cancer.
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