Fig. 1
R159 treatment inhibits gp130-Y814/SFK module in primary synovial cells and demonstrates improved ADME profile compared to previously developed analogs. (a) Pharmacokinetic characteristics of small molecule drug R805 and its analog, R159. TPSA (total polar surface area) range 60–140 Å2 is considered good solubility and permeability. cLogP and cLogD show predicted water solubility; cLogP less than 3 and cLogD less than 1 are considered favorable for water solubility. pKa indicates the ionization state of the compound at given pH. RLM (rat liver microsome)/HLM (human liver microsome) show stability in rat/human liver microsomes; %LBF shows the clearance attributed to liver blood flow. KS shows the solubility constant at a pH 7.4. MDCK (Madin-Darby canine kidney) WT and MDCK MDR1 cells are used to test drug transport and permeability. A higher Papp value in the A-B direction suggests better absorption potential and a higher Papp value in the B-A direction can indicate strong efflux activity. EER shows an efflux ratio; an EER equal to or close to 1 suggests balanced influx and efflux, indicating that efflux is not significantly hindering the compound’s permeability. (b) Western blots for phosphorylated gp130-Y814 in human synovial fibroblasts treated with or without OSM (10ng/mL) and R159 (10 µM) for 4 h, n = 4. (c) Western blots for phosphorylated SRC in human synovial fibroblasts treated with or without OSM (10ng/mL) and R159 (10 µM) for 4 h, n = 4. One-way ANOVA with multiple comparisons with Tukey test was used for statistical analysis of (b) and (c); p-values less than 0.05 were considered significant. Original blots for (b) and (c) are presented in Supplementary Fig. 1.
