J Med Chem: Dual PROTAC is here: Chinese scholars first proposed a new concept of dual-targeted degradation (Dual PROTACs) drug design

Proteolysis targeting chimera (PROTAC) is a bifunctional small molecule, in which the target protein ligand and E3 ubiquitin ligase ligand are linked together by a linking arm.

Recently, Professor Li Hua and Associate Professor Zhou Yirong from Tongji School of Pharmacy, Huazhong University of Science and Technology, and Professor Chen Lixia from Wuya Innovation College of Shenyang Pharmaceutical University, as co-corresponding authors, published the title: Rational Design and Synthesis of Novel in Journal of Medicinal Chemistry, the top journal of medicinal chemistry.

This research creatively proposes a new concept for the design of dual-targeted degradation drugs (Dual PROTACs), using the existing EGFR inhibitor Gefitinib and PARP inhibitor Olaparib as raw materials to synthesize different link lengths and different E3 ligases (CRBN- and VHL- ) The recruited EGFR and PARP protein dual target degradation chimeric molecules (Dual PROTACss), and successfully degrade both EGFR and PARP proteins in cancer cells at the cellular level.

Schematic diagram of the design concept: The "Dual PROTACs" used two kinds of martial arts to defeat the King of the Golden Wheel (tumor).

In addition to drug resistance, single-target therapeutic drugs can also lead to reduced efficacy and reduced patient quality of life due to side effects and tissue toxicity.

Another strategy to improve efficacy is to design a single hybrid molecule that fuses two or more pharmacophores to target two or more anti-tumor epitopes or targets at the same time.

Inspired by the great success of dual-target drugs, especially bispecific antibodies, Professor Li Hua et al.

Dual PROTACs design concept.

Molecular structure and synthesis of Dual PROTACs.

Dual PROTACs simultaneously degrade EGFR and PARP in cancer cells at the cellular level.

At present, the clinical treatment of two different target inhibitors in combination, and even the treatment of some dual-specific antibodies, can be replaced by the strategy of this study to design a corresponding single Dual PROTACs molecule for dual-targeted degradation.

In the field of cancer combination therapy, Dual PROTACs can be quickly applied.

Of course, in addition to the obvious advantages of Dual PROTACs, the increase in molecular weight will cause certain problems in druggability and pharmacokinetics.
To solve these problems, there may be two directions.
One is to deliver nano-drug delivery systems to improve drug absorption, and the other is to find ways to simplify the inhibitor part and retain the smallest pharmacophore.
These are worthy of further study.

Postdoctoral Zheng Mengzhu, research assistant Huo Junfeng, and doctoral student Gu Xiaoxia of Huazhong University of Science and Technology Tongji School of Pharmacy are the co-first authors.
Professor Li Hua, Associate Professor Zhou Yirong of Huazhong University of Science and Technology Tongji School of Pharmacy and Professor Chen Lixia of Wuya Innovation College of Shenyang Pharmaceutical University are co-corresponding authors .

Original source:

Mengzhu Zheng, et al.
Rational Design and Synthesis of Novel Dual PROTACs for Simultaneous Degradation of EGFR and PARP.
J.
Med.
Chem.
2021.