Recent advances in developing targeted protein degraders

Binbin Cheng; Hongqiao Li; Xiaopeng Peng; Jianjun Chen; Chuxiao Shao; Zhihua Kong

doi:10.1016/j.ejmech.2024.117212

Recent advances in developing targeted protein degraders

Eur J Med Chem. 2024 Dec 27:284:117212. doi: 10.1016/j.ejmech.2024.117212. Online ahead of print.

Authors

Binbin Cheng¹, Hongqiao Li², Xiaopeng Peng³, Jianjun Chen⁴, Chuxiao Shao⁵, Zhihua Kong⁶

Affiliations

¹ Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University, Huangshi, 435003, China; Central Laboratory, Wenzhou Medical University Lishui Hospital, Lishui People's Hospital, Lishui, Zhejiang, 323000, China.
² The Central Hospital of Huangshi, Huangshi, 435000, China.
³ College of Pharmacy, Gannan Medical University, Ganzhou, 314000, China. Electronic address: [email protected].
⁴ Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
⁵ Central Laboratory, Wenzhou Medical University Lishui Hospital, Lishui People's Hospital, Lishui, Zhejiang, 323000, China. Electronic address: [email protected].
⁶ Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, FoShan, 528200, China. Electronic address: [email protected].

PMID: 39736199
DOI: 10.1016/j.ejmech.2024.117212

Abstract

Targeted protein degradation (TPD) represents a promising therapeutic approach, encompassing several innovative strategies, including but not limited to proteolysis targeting chimeras (PROTACs), molecular glues, hydrophobic tag tethering degraders (HyTTD), and lysosome-targeted chimeras (LYTACs). Central to TPD are small molecule ligands, which play a critical role in mediating the degradation of target proteins. This review summarizes the current landscape of small molecule ligands for TPD molecules. These small molecule ligands can utilize the proteasome, lysosome, autophagy, or hydrophobic-tagging system to achieve the degradation of target proteins. The article mainly focuses on introducing their design principles, application advantages, and potential limitations. A brief discussion on the development prospects and future directions of TPD technology was also provided.

Keywords: HyTTD; LYTACs; Molecular glues; PROTACs; Small molecule ligands; Targeted protein degradation.

Publication types

Review