Development of a PROTAC Targeting Chk1.

A series of Chk1 degraders were designed and synthesized. The degraders were developed through the conjugation of a promiscuous kinase binder and thalidomide. One of the degraders PROTAC-2 was able to decrease Chk1 levels in a concentration-dependent manner in A375 cells.

Selective Smurf1 E3 ligase inhibitors that prevent transthiolation.

Smurf1 is a HECT E3 ligase that is genetically micro-duplicated in human patients and is associated with osteoporosis. Smurf1 mice on the other hand show an increase in bone density as they age, while being viable and fertile. Therefore, Smurf1 is a promising drug target to treat osteoporosis.

Discovery of covalent enzyme inhibitors using virtual docking of covalent fragments.

Here we present a virtual docking screen of 1648 commercially available covalent fragments, and identified covalent inhibitors of cysteine protease cathepsin L. These inhibitors did not inhibit closely related protease cathepsin B. Thus, we have established virtual docking of covalent fragments as an approach to discover covalent enzyme inhibitors.