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

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 factor, GSPT1 to
achieve its potent anticancer activity. Our study provides the first
example that simple structural modifications can convert a bona fide
PROTAC degrader into a molecular glue compound, which has a completely
different mechanism of action.