2008 has been an interesting year. The drug-discovery industry has shrunk dramatically in market capitalization, as well as, I suspect, in the number of companies. One of the pioneers of biotech fragment-based drug discovery, SGX Pharmaceuticals, was acquired by Lilly for $64 million in August; hopefully the fragment-based know-how will percolate throughout Lilly. I thought I’d end this year by highlighting a recent communication from SGX published in the first 2009 issue of Bioorganic and Medicinal Chemistry Letters. The paper was accepted on 18 August, two days before the merger with Lilly was completed.
SGX relied heavily on crystallographic discovery of fragments, and their efforts towards inhibitors of JAK-2, a protein tyrosine kinase target for myloproliferative disorders, began by crystallizing the protein and performing fragment-soaking experiments. A bromoaminoindazole fragment with a mid-micromolar IC50 and high ligand efficiency was found to bind to the hinge region of the kinase. Examination of the crystal structure revealed a hydrophobic groove nearby, and replacement of the bromine by a phenyl group boosted the affinity by a factor of 25. Further elaboration of the phenyl group improved the IC50 to 78 nM, more than 500-fold better than the initial fragment. The molecule also exhibited respectable (38-fold) selectivity over JAK-3. Although ligand efficiency fell throughout the optimization process, it remained high; the final molecule remains relatively small and does not appear to violate Lipinski’s Rule of Five. There is no mention of cell activity or other pharmaceutical properties, but the authors do promise future publications.
In closing out this year, we would like to thank everyone for reading, and especially for commenting. Please pass along any fragment news or events and we will get the word out. May you all have a happy and productive 2009!