Leveraging the C-Map for discovery of compound synergism. An investigator-derived gene-expression signature is generated. In this case, a gene signature distinguishing vehicle-treated (Veh) versus parthenolide-treated (PTL) cells is derived using genome-wide expression profiling. This signature contains both the on-target alterations in expression with PTL as well as the alterations of expression induced with the cytoprotective response. This signature is then imported into the C-Map, a large reference collection of small molecules profiled in human cancer cell lines by expression microarrays. A pattern-matching algorithm scores each reference profile for the direction and the strength of enrichment with the investigator-derived query. In the work by Hassane et al,¹  as expected, the C-Map instance of AML-treated PTL scores as the top positive connection, while multiple instances of PI3K/mTOR inhibitors score as negative connections. The authors hypothesized that these negatively connected molecules might reverse the cytoprotective component of the PTL signature.