Applications and research advances of PROTAC drugs
- VernacularTitle:PROTAC药物的应用与研究进展
- Author:
Zhaoping PAN
1
;
Gu HE
2
;
Fengbo WU
1
Author Information
1. Dept. of Pharmacy，West China Hospital，Sichuan University，Chengdu 610041，China
2. Laboratory of Dermatology，West China Hospital，Sichuan University，Chengdu 610041，China
- Publication Type:Journal Article
- Keywords:
PROTACs;
vepdegestrant;
clinical translation;
innovative strategies
- From:
China Pharmacy
2026;37(18):2462-2470
- CountryChina
- Language:Chinese
-
Abstract:
Proteolysis-targeting chimeras （PROTACs）， with their “event-driven” pharmacological mode， can mediate the degradation of target proteins through the ubiquitin-proteasome system， providing a new solution to the challenges of “undruggable” targets and tumor drug resistance. With the approval of vepdegestrant by U.S. FDA in 2026 for estrogen receptor-positive advanced or metastatic breast cancer， PROTACs have officially achieved clinical translation. Currently， multiple candidate drugs targeting androgen receptor， Bruton’s tyrosine kinase， epidermal growth factor receptor and interleukin-1 receptor-associated kinase 4 have entered various phases of clinical trials， covering multiple therapeutic fields such as tumors and inflammatory diseases. However， PROTACs still face significant drug development bottlenecks： their high molecular weight leads to defects in physicochemical properties， resulting in insufficient membrane permeability and oral bioavailability； the inherent “HOOK effect” increases the difficulty of formulating clinical dosing regimens； meanwhile， loss or mutation of E3 ubiquitin ligase expression can induce acquired drug resistance， and the currently available E3 ligand resources are relatively limited. To overcome these limitations， innovative research and development strategies such as controllable activation modification， aptamer or antibody conjugation， nanodelivery and multi-target multivalent design have been developed. Different technologies have their own advantages， but they are also accompanied by new drug development shortcomings， such as limited penetration of photosensitive groups， insufficient stability of conjugated molecules and difficulties in large-scale production of nanoformulations. Artificial intelligence-assisted molecular design， expansion of novel E3 ubiquitin ligase ligands and broadening of disease indications are important future development directions， which may provide references for the molecular optimization， preclinical development and clinical translation of PROTACs.
