pIC50 values for sodium fluorescein (10 uM) uptake in OATP1B3-transfected CHO cells
Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate more ..
BioActive Compounds: 66
Title: Structure-based identification of OATP1B1/3 inhibitors.
Abstract: Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 microM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 microM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.
ChEMBL Target ID: 104062
Target Type: SINGLE PROTEIN
Pref Name: Solute carrier organic anion transporter family member 1B3
Synonyms: Liver-specific organic anion transporter 2;LST-2;OATP-8;Organic anion transporter 8;Organic anion-transporting polypeptide 8;Solute carrier family 21 member 8;Solute carrier organic anion transporter family member 1B3;
Gene Name: LST2 ;OATP1B3;OATP8SLC21A8;SLCO1B3;
Protein Accession: Q9NPD5;
Protein GI: 27734563;
Organism: Homo sapiens
Tax ID: 9606
Target Classification: transporter electrochemical slc slc21
Confidence: Homologous single protein target assigned
Relationship Type: Homologous protein target assigned
Categorized Comment - additional comments and annotations
Assay Type: ADME
Assay Data Source: Scientific Literature
BAO: Assay Format: cell-based format
Assay Cell Type: CHO
Assay Test Type: In vitro
* Activity Concentration.
Data Table (Concise)