In summary, the small-molecule p53 MDM2 binding inhibitors described in the literature so far have shown modest potency, lack of selectivity and inadequate pharmacological properties.
Our results indicate that although these compounds are structural analogs, their potency of cytotoxicity, selectivity against NF-κB signaling pathway, and their inhibitory effects against protein and nucleic acid synthesis are different.
Functional proliferation and clonogenic assays were performed (i) to assess PDGFR-mediated survival and proliferation in fibroblasts and endothelial cells after SU9518 (small molecule inhibitor of PDGF receptor tyrosine kinase); (ii) to test the potency und selectivity of the PDGF RTK inhibitor after stimulation with PDGF isoforms (-AB, -AA, -BB) and VEGF+bFGF.
A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen.
HU-308 (5, Fig. 2A) was chosen as the query molecule for the virtual screen due to its high potency and degree of selectivity for CB2R over the CB1R (> 400 fold).
Inhibition studies with these compounds showed that two of them not only retained most of the potency and selectivity of the best analogue of the earlier series, but also showed improved membrane permeability based on data from a cell-based assay.
The SAR studies revealed that the rigidifying of appropriate molecules enabled modulation of the potency and selectivity of the HCA2 receptor activation.
The authors conclude that, taken together, the desirable potency of 5 and selectivity of 6 in regards to the parasite kinase, the GSK-3β selectivity of 8, and the desirable cytotoxicity data of 7 all contribute to excellent starting points for future TbGSK inhibitors.
Although used in numerous investigations in vitro and in vivo, there have been surprisingly few tests of the potency and selectivity of these compounds in cells.
Since then, a lot of efforts have been done to increase potency and selectivity of this kind of compounds, conforming a great variety of diverse chemical compounds with interesting pharmacological profiles [21].
Because of the high potency and selectivity of S66, we used it to investigate the relevance of the Ca2+ entry mechanism to VSMC migration and proliferation.
