Further optimization yielded an inhibitor with IC50 of 0.060 μM.
Structure activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding.
For BI8622, we performed multiple ubiquitination assays in the presence of different concentrations of inhibitor; this yielded an IC50 value of 6.8 μM, similar to that obtained in vitro (Supplementary Fig S4E).
In an accompanying experiment, we treated 621.102 cells for 6 days with the mTORC1 inhibitor rapamycin, which yielded an IC50 of 5.5±2.3 nM (n=3).
Finally, we explored the base case model with the addition of effects on lipids, based on the estimates reported in the meta-analysis by Monami et al. 28 Our meta-analysis yielded an estimate of the DPP-4 inhibitor class effect on HbA1c of −0.66% (−0.71%, −0.62%), for a population with a baseline HbA1c of 8.0% (τ=0.02).
Enoxaparin [ 7], a low molecular weight heparin commonly used for treatment of patients with acute deep vein thrombosis and pulmonary embolism, binds to antithrombin and changes its conformation to yield an effective inhibitor primarily of factor Xa. If enoxaparin and DAA are combined, this might result in a summation of anticoagulant effects.
Exposure of C6 to either SOC inhibitor yielded a pattern of ATP response close to that observed in Ca2+-free PSS (Fig. 1B) with attenuation of the prolonged component of [Ca2+]i.
In contrast, control treatment of cells with actinomycin D, an inhibitor of RNA polymerase, did yield the expected strong decrease of EU staining throughout the cell (data not shown and [32]).
Bioassay-driven purification and structural determination of compounds from plant sources have yielded a number of pump inhibitors which acted against gram positive bacteria.
Indeed, screening CpCDPK1 against a library of kinase inhibitors yielded a set of the pyrazolopyrimidine derivatives (PP1-derivatives) with IC50 values of < 10 nM.
