This one comes from a NCI group. Starting with a database of 3.5 million compounds, 175 prospective candidates were finally selected for inhibition of Met kinase by virtual screening based on filtering by size, log P, polarity, h-bond donors and acceptors etc. The 175 compounds were docked by GOLD and 70 were selected on the basis of force-field calculated protein-ligand interaction energies (always a risky endeavor, but for a similar series, errors may cancel). For paring down the compound set, an empirical pharmacophore based on the usual kinase interactions (eg. h-bonding to hinge residues and h-bonding to a crucial Tyr to keep the kinase locked in the inactive conformation) was used.
The 70 compounds bought from vendors were assayed in cell-free Met assays as well as HGF (hepatocyte growth factor) induced Met activation. 3 compounds were chosen with modest Met inhibition IC50 values of 0.6 and 40 µM. The IC50s for the intact cells were 30, 50 and 30 µM. In spite of this less than stellar inhibition performance, the three were tested for the inhibition of other kinases and found to inhibit VEGFR and FGFR to similar extents. Since the single-kinase inhibition paradigm seems to be called into question these days, one might as well diversify. The different inhibition values were rationalized on the basis of hydrogen bonding and other interactions (or the lack thereof) by docking. Wisely, docking and docking scores were not used for judging binding affinity, just the orientations of the compounds in the active sites.
The flavone-like looks of the compounds make me quite suspicious about PK and Tox. Only time will tell. But Met is emerging as a valuable target.
Reference: Megan L. Peach, Nelly Tan, Sarah J. Choyke, Alessio Giubellino, Gagani Athauda, Terrence R. Burke, Jr., Marc C. Nicklaus and Donald P. Bottaro (2009) Directed Discovery of Agents Targeting the Met Tyrosine Kinase Domain by Virtual Screening J. Med. Chem ASAP