Biology subjects
Publications and source records attributed to Chuong, P..
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. The developed probes can be useful for the development of selective and more potent Chk1 degraders.
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. This paper reports the discovery, synthesis, and biochemical characterization of highly selective Smurf1 inhibitors. We show that these compounds inhibit the catalytic HECT domain of Smurf1 with 500 nM IC50, but they do not inhibit closely related Smurf2 ligase, which is 80% identical to Smurf1. We show that Smurf1 inhibitors act by preventing the trans-thiolation reaction between Smurf1 and E2[~]Ub thioesters. Our preliminary studies show that the C-lobe of Smurf1 alone does not contribute to the observed high selectivity of Smurf1 inhibitors.