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

preprint
submitted on 17.02.2021, 17:56 and posted on 18.02.2021, 12:58 by Mengzhu Zheng, Junfeng Huo, Xiaoxia Gu, Canrong Wu, Qingzhe Zhang, Wang Wang, Yang Liu, Yu Liu, Xuechen Zhou, Lixia Chen, Yirong Zhou, Hua Li
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.

Funding

National Natural Science Foundation of China grant numbers 81773637, U1803122, and 81903863

National Mega-project for Innovative Drugs (grant number 2019ZX09721001-004-007, China)

Chunhui Program-Cooperative Research Project of the Ministry of Education

Natural Science Foundation of Hubei Province (No. 2020CFB642)

100 Talents Program of the Hubei Provincial Government

Liaoning Revitalization Talents Program (No. XLYC1807182)

Liaoning Province Natural Science Foundation (No. 2020-MZLH-31)

History

Email Address of Submitting Author

li_hua@hust.edu.cn

Institution

Huazhong University of Science and Technology

Country

China

ORCID For Submitting Author

0000-0003-1903-836X

Declaration of Conflict of Interest

No conflict of interest

Version Notes

version no. 1

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