Proteolysis-Targeting Chimeras (PROTACs) in Cancer Therapy: Present and Future

Rui Li; Miao Liu; Zhenya Yang; Jiao Li; Yuxin Gao; Ruirong Tan

doi:10.3390/molecules27248828

Proteolysis-Targeting Chimeras (PROTACs) in Cancer Therapy: Present and Future

Molecules. 2022 Dec 12;27(24):8828. doi: 10.3390/molecules27248828.

Authors

Rui Li¹, Miao Liu², Zhenya Yang³, Jiao Li⁴, Yuxin Gao¹, Ruirong Tan⁴

Affiliations

¹ Sichuan Cancer Hospital and Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.
² Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410083, China.
⁴ Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China.

Abstract

The PROteolysis TArgeting Chimeras (PROTACs) is an innovative technique for the selective degradation of target proteins via the ubiquitin-proteasome system. Compared with traditional protein inhibitor drugs, PROTACs exhibit advantages in the efficacy and selectivity of and in overcoming drug resistance in cancer therapy, providing new insights into the discovery of anti-cancer drugs. In the last two decades, many PROTAC molecules have been developed to induce the degradation of cancer-related targets, and they have been subjected to clinical trials. Here, we comprehensively review the historical milestones and latest updates in PROTAC technology. We focus on the structures and mechanisms of PROTACs and their application in targeting tumor-related targets. We have listed several representative PROTACs based on CRBN, VHL, MDM2, or cIAP1 E3 ligases, and PROTACs that are undergoing anti-cancer clinical trials. In addition, the limitations of the current research, as well as the future research directions are described to improve the PROTAC design and development for cancer therapy.

Keywords: PROTACs; cancer therapy; protein degradation; targeted protein degradation.

Publication types

Review

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Humans
Neoplasms* / drug therapy
Proteasome Endopeptidase Complex / metabolism
Proteolysis
Ubiquitin / metabolism

Substances

Proteasome Endopeptidase Complex
Ubiquitin
Antineoplastic Agents

Grants and funding

This research was supported by the Oncology Medical-Industrial Innovation Fund Project of University of Electronic Science and Technology, Sichuan Cancer Hospital (Grant No. ZYGX2021YGCX020), the Sichuan Cancer Hospital Youth Fund Project (Grant No. YB2021035), the National Natural Science Foundation of China (Grant No. 82204695), the Sichuan Provincial Research Institutes Basic Research Operations Fund Project (Grant No. A-2022N-Z-2), and the Sichuan Academy of Traditional Chinese Medicine Research Project (Grant No. QNCJRSC2022-9).