The Chemistry Core has the key mission of transforming uHTS hits on important molecular targets to proof-of-concept molecular probes with activities in cellular or whole animal systems. The Core is capable of supporting 3-4 probe optimization programs in parallel, with 6-8 targets approached per year, in addition to supporting several pathway profiling efforts to identify the biochemical targets of hits deriving from phenotypic or certain cell-based screens. The Chemistry Core has been built on a scaleable model where highly experienced PIs can increase capacity for probe optimization support rapidly as funding increases.

In the past year, the Chemistry Core has performed hit optimization studies on S1P1 agonists and antagonists, S1P2 agonists, S1P3 agonists, SF-1 inhibitors, RORa inhibitors, and MMP-13 inhibitors, among others. Several of these efforts have already led to optimized probe compounds (e.g., SF-1 inhibitor). Hit profiling efforts using activity-based protein profiling (ABPP) technology have identified isoform-selective probes of MMP-8 and MMP13, the latter of which serves as the starting point for a medicinal chemistry probe optimization effort. In addition, detailed profiling of SF-1 and RORa inhibitor HTS hits as well as synthetic analogs using a Gal4 nuclear receptor panel containing all known human nuclear receptors has led to the identification of selective RAR inverse agonist and SHP activator probes.