Targeted protein degrader development for cancer: advances, challenges, and opportunities

Yuan Fang; Shuhang Wang; Songzhe Han; Yizhou Zhao; Cunjing Yu; Huaqing Liu; Ning Li

doi:10.1016/j.tips.2023.03.003

Targeted protein degrader development for cancer: advances, challenges, and opportunities

Trends Pharmacol Sci. 2023 May;44(5):303-317. doi: 10.1016/j.tips.2023.03.003.

Authors

Yuan Fang¹, Shuhang Wang¹, Songzhe Han², Yizhou Zhao², Cunjing Yu³, Huaqing Liu², Ning Li⁴

Affiliations

¹ Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
² Department of Chemistry, BeiGene (Beijing) Co. Ltd, Beijing 100020, China.
³ Translational Discovery, Research, and Medicine, BeiGene (Beijing) Co. Ltd, Beijing 100020, China.
⁴ Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address: ncctrials@cicams.ac.cn.

PMID: 37059054
DOI: 10.1016/j.tips.2023.03.003

Abstract

Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used in clinical settings for decades. However, many cancer-related targets are proteins without catalytic activity and are difficult to target using traditional occupancy-driven inhibitors. Targeted protein degradation (TPD) is an emerging therapeutic modality that has expanded the druggable proteome for cancer treatment. With the entry of new-generation immunomodulatory drugs (IMiDs), selective estrogen receptor degraders (SERDs), and proteolysis-targeting chimera (PROTAC) drugs into clinical trials, the field of TPD has seen explosive growth in the past 10 years. Several challenges remain that need to be tackled to increase successful clinical translation of TPD drugs. We present an overview of the global landscape of clinical trials of TPD drugs over the past decade and summarize the clinical profiles of new-generation TPD drugs. In addition, we highlight the challenges and opportunities for the development of effective TPD drugs for future successful clinical translation.

Keywords: IMiD; PROTAC; SERD; cancer; protein degradation.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Drug Delivery Systems
Humans
Neoplasms* / drug therapy
Proteolysis
Proteolysis Targeting Chimera

Substances

Proteolysis Targeting Chimera