Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders.

ABSTRACT: Inducing protein degradation by proteolysis targeting chimeras (PROTACs) has gained tremendous momentum for its promise to discover and develop new therapies. Based upon our previously reported PROTAC MDM2 degraders, we have designed and synthesized additional analogues. Surprisingly, we found that simple structural modifications of MD-222, a bona fide MDM2 PROTAC degrader, converts it into a "molecular glue", as exemplified by MG-277. MG-277 induces only moderate MDM2 degradation and fails to activate wild-type p53 but is highly potent in inhibition of tumor cell growth in a p53-independent manner. Our mechanistic investigation established that MG-277 is not a PROTAC MDM2 degrader but instead works as a molecular glue, inducing degradation of a translation termination

SUBMITTER: Yang J 

PROVIDER: S-EPMC7354697 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature