Hsp90 and fragments

Some targets seem particularly amenable to fragment-based approaches. Protein kinases are one example. Another is the N-terminal ATP binding domain of Hsp90, a widely pursued anti-cancer target: at least two fragment-derived compounds against this target are currently in the clinic. At FBLD 2008 in San Diego last year, so many talks discussed this protein that it became a running gag (one speaker promised at the outset not to talk about it, then slipped in a few slides). A recent paper in ChemMedChem provides a particularly clear example of a multidisciplinary fragment-growing approach against this target.

The researchers, mostly from Evotec, started with a high-concentration biochemical displacement assay to screen 20,000 fragments against Hsp90. A relatively potent aminopyrimidine (compound 1, below) was characterized crystallographically, and this structure was then used to run a virtual screen of 3.8 million commercially available molecules using the program GOLD 3.0.1. Some of the resulting hits were purchased and tested, including compound 3, which showed sub-micromolar biochemical activity but no cell-based activity. Subsequent modeling and medicinal chemistry led to compound 19, which, in addition to mid-nanomolar biochemical activity, also displayed submicromolar cell activity in A549 and HCT116 cancer cell lines.


In addition to compound 1, a number of other fragments containing the aminopyrimidine substructure were also identified as hits. This moiety seems to be a privileged pharmacophore for Hsp90: for a fun read, check out this 2007 paper from researchers at Abbott, in which fragments are linked together in a couple different ways as well as grown. As in the more recent paper, the protein displays a remarkable degree of flexibility to accommodate small molecule binders.