Biological and Medicinal Chemistry

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

Hua Li Huazhong University of Science and Technology

Abstract

Inspired by the success of dual targeting drugs, especially bispecific antibodies, we propose to combine the concept of 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 have been rationally designed and prepared. A convergent synthetic strategy has been utilized to achieve high synthetic efficiency. These dual protac structures are characterized by 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 ligand were used as substrates to synthesize novel dual protacs. They successfully degraded both EGFR and 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.

Version notes

version no. 1

Content

Thumbnail image of dual_protac manuscript.pdf
download asset dual_protac manuscript.pdf 1 MB [opens in a new tab]

Supplementary material

Thumbnail image of Supplementary Information.pdf
download asset Supplementary Information.pdf 4 MB [opens in a new tab]
Supplementary Information