Figure 2.

Chemical design of PINADs. (a) Synthetic design of PDS family of PINADs. (b) Synthetic design of MTDB family of PINADs. See Supporting Information for complete synthesis procedures; characterization PDS has been previously functionalized on its central pyridine core, and it was shown that this functionalization does not abolish its binding ability.¹⁹ As such, we chose to modify it on this position. MTDB, on the other hand, has not been further modified previously. However, as it was discovered through molecular docking, the docking pose provided insight into where the molecule could be functionalized without compromising its binding affinity. We thus chose to transform a terminal ethyl ester into a propargylic amide (more stable in cellular environments than an ester), which was in turn functionalized with the azide-degraders.