Rational Design and Synthesis of Novel Dual PROTACs for Simultaneous Degradation of EGFR and PARP

Inspired
by the success of dual-targeting drugs, especially bispecific
antibodies, we propose to combine the concept of proteolysis targeting
chimera (PROTAC) and dual targeting to design and synthesize dual
PROTAC molecules with the function of degrading two completely different
types of targets simultaneously. A library of novel dual-targeting
PROTAC molecules has been rationally designed and prepared. A convergent
synthetic strategy has been utilized to achieve high synthetic efficiency.
These dual PROTAC structures are characterized using trifunctional
natural amino acids as star-type core linkers to connect two independent
inhibitors and E3 ligands together. In this study, gefitinib, olaparib,
and CRBN or VHL E3 ligands were used as substrates to synthesize novel
dual PROTACs. They successfully degraded both the epidermal growth
factor receptor (EGFR) and poly­(ADP-ribose) polymerase (PARP) simultaneously
in cancer cells. Being the first successful example of dual PROTACs,
this technique will greatly widen the range of application of the
PROTAC method and open up a new field for drug discovery.