Journal
FRONTIERS IN PHARMACOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2020.00140
Keywords
phenylketonuria; steatohepatitis; non-alcoholic steatohepatitis; solute carrier; high throughput screening; HTS
Categories
Funding
- Australian Research Council [DP180101702]
- National Health and Medical Research Council [1128442]
- Diabetes Australia
- National Health and Medical Research Council of Australia [1128442] Funding Source: NHMRC
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Lack of B(0)AT1 (SLC6A19) partially protects mice against the onset of non-alcoholic steatohepatitis (NASH). To achieve a similar outcome through pharmacological treatment, we improved previously identified inhibitors of B(0)AT1 by medicinal chemistry and identified second generation inhibitors by high through-put screening. Modified diarylmethine compounds inhibited B(0)AT1 with IC50 values ranging from 8-90 mu M. A second generation of inhibitors was derived from high-throughput screening and showed higher affinity (IC50 of 1-15 mu M) and strong selectivity against amino acid transporters with similar substrate specificity, such as ASCT2 (SLC1A5) and LAT1 (SLC7A5). All compounds were unrelated to B(0)AT1 substrates, but were likely to bind in the vicinity of the substrate binding site.
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