PMID- 36006861
OWN - NLM
STAT- MEDLINE
DCOM- 20220909
LR  - 20221009
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 65
IP  - 17
DP  - 2022 Sep 8
TI  - Progress and Challenges in Targeted Protein Degradation for Neurodegenerative 
      Disease Therapy.
PG  - 11454-11477
LID - 10.1021/acs.jmedchem.2c00844 [doi]
AB  - Neurodegenerative diseases (NDs) are currently incurable diseases that cause 
      progressive degeneration of nerve cells. Many of the disease-causing proteins of 
      NDs are "undruggable" for traditional small-molecule inhibitors (SMIs). None of 
      the compounds that attenuated the amyloid-beta (Abeta) accumulation process have 
      entered clinical practice, and many phase III clinical trials of SMIs for 
      Alzheimer's disease (AD) have failed. In recent years, emerging targeted protein 
      degradation (TPD) technologies such as proteolysis-targeting chimeras (PROTACs), 
      lysosome-targeting chimaeras (LYTACs), and autophagy-targeting chimeras (AUTACs) 
      with TPD-assistive technologies such as click-formed proteolysis-targeting 
      chimeras (CLIPTACs) and deubiquitinase-targeting chimera (DUBTAC) have developed 
      rapidly. In vitro and in vivo experiments have also confirmed that TPD technology 
      can target the degradation of ND pathogenic proteins, bringing hope for the 
      treatment of NDs. Herein, we review the latest TPD technologies, introduce their 
      targets and technical characteristics, and discuss the emerging TPD technologies 
      with potential in ND research, with the hope of providing a new perspective for 
      the development of TPD technology in the NDs field.
FAU - Fang, Yingxu
AU  - Fang Y
AUID- ORCID: 0000-0002-5266-893X
AD  - Joint Research Institution of Altitude Health, Department of Respiratory and 
      Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, 
      National Clinical Research Center for Geriatrics, West China Hospital, Sichuan 
      University, Chengdu 610041, Sichuan, China.
AD  - Targeted Tracer Research and Development Laboratory, Institute of Respiratory 
      Health, Frontiers Science Center for Disease-Related Molecular Network, West 
      China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
FAU - Wang, Jiaxing
AU  - Wang J
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of 
      Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
FAU - Zhao, Min
AU  - Zhao M
AD  - Joint Research Institution of Altitude Health, Department of Respiratory and 
      Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, 
      National Clinical Research Center for Geriatrics, West China Hospital, Sichuan 
      University, Chengdu 610041, Sichuan, China.
AD  - Targeted Tracer Research and Development Laboratory, Institute of Respiratory 
      Health, Frontiers Science Center for Disease-Related Molecular Network, West 
      China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
AD  - Tianfu Jincheng Laboratory, Chengdu 610041, Sichuan, China.
FAU - Zheng, Qinwen
AU  - Zheng Q
AD  - Joint Research Institution of Altitude Health, Department of Respiratory and 
      Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, 
      National Clinical Research Center for Geriatrics, West China Hospital, Sichuan 
      University, Chengdu 610041, Sichuan, China.
FAU - Ren, Changyu
AU  - Ren C
AD  - Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu 611130, Sichuan, 
      China.
FAU - Wang, Yuxi
AU  - Wang Y
AUID- ORCID: 0000-0002-4056-5829
AD  - Joint Research Institution of Altitude Health, Department of Respiratory and 
      Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, 
      National Clinical Research Center for Geriatrics, West China Hospital, Sichuan 
      University, Chengdu 610041, Sichuan, China.
AD  - Targeted Tracer Research and Development Laboratory, Institute of Respiratory 
      Health, Frontiers Science Center for Disease-Related Molecular Network, West 
      China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
AD  - Tianfu Jincheng Laboratory, Chengdu 610041, Sichuan, China.
FAU - Zhang, Jifa
AU  - Zhang J
AUID- ORCID: 0000-0001-8618-9200
AD  - Joint Research Institution of Altitude Health, Department of Respiratory and 
      Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, 
      National Clinical Research Center for Geriatrics, West China Hospital, Sichuan 
      University, Chengdu 610041, Sichuan, China.
AD  - Targeted Tracer Research and Development Laboratory, Institute of Respiratory 
      Health, Frontiers Science Center for Disease-Related Molecular Network, West 
      China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
AD  - Tianfu Jincheng Laboratory, Chengdu 610041, Sichuan, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20220825
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Proteins)
SB  - IM
MH  - Chimera/metabolism
MH  - Humans
MH  - Lysosomes/metabolism
MH  - *Neurodegenerative Diseases/drug therapy/metabolism
MH  - Proteins/metabolism
MH  - Proteolysis
EDAT- 2022/08/26 06:00
MHDA- 2022/09/11 06:00
CRDT- 2022/08/25 13:46
PHST- 2022/08/26 06:00 [pubmed]
PHST- 2022/09/11 06:00 [medline]
PHST- 2022/08/25 13:46 [entrez]
AID - 10.1021/acs.jmedchem.2c00844 [doi]
PST - ppublish
SO  - J Med Chem. 2022 Sep 8;65(17):11454-11477. doi: 10.1021/acs.jmedchem.2c00844. 
      Epub 2022 Aug 25.