PMID- 36086898
OWN - NLM
STAT- MEDLINE
DCOM- 20221209
LR  - 20230413
IS  - 1098-1128 (Electronic)
IS  - 0198-6325 (Print)
IS  - 0198-6325 (Linking)
VI  - 43
IP  - 1
DP  - 2023 Jan
TI  - KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological 
      properties and therapeutic potential.
PG  - 237-287
LID - 10.1002/med.21925 [doi]
AB  - The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is 
      considered the master regulator of the phase II antioxidant response. It controls 
      a plethora of cytoprotective genes related to oxidative stress, inflammation, and 
      protein homeostasis, among other processes. Activation of these pathways has been 
      described in numerous pathologies including cancer, cardiovascular, respiratory, 
      renal, digestive, metabolic, autoimmune, and neurodegenerative diseases. 
      Considering the increasing interest of discovering novel NRF2 activators due to 
      its clinical application, initial efforts were devoted to the development of 
      electrophilic drugs able to induce NRF2 nuclear accumulation by targeting its 
      natural repressor protein Kelch-like ECH-associated protein 1 (KEAP1) through 
      covalent modifications on cysteine residues. However, off-target effects of these 
      drugs prompted the development of an innovative strategy, the search of 
      KEAP1-NRF2 protein-protein interaction (PPI) inhibitors. These innovative 
      activators are proposed to target NRF2 in a more selective way, leading to 
      potentially improved drugs with the application for a variety of diseases that 
      are currently under investigation. In this review, we summarize known KEAP1-NRF2 
      PPI inhibitors to date and the bases of their design highlighting the most 
      important features of their respective interactions. We also discuss the 
      preclinical pharmacological properties described for the most promising 
      compounds.
CI  - (c) 2022 The Authors. Medicinal Research Reviews published by Wiley Periodicals 
      LLC.
FAU - Crisman, Enrique
AU  - Crisman E
AD  - Instituto de Quimica Medica, Consejo Superior de Investigaciones Cientificas 
      (IQM-CSIC), Madrid, Spain.
AD  - Instituto de Investigacion Sanitaria La Princesa, Hospital Universitario de la 
      Princesa, Madrid, Spain.
AD  - Instituto Teofilo Hernando y Departamento de Farmacologia y Terapeutica, Facultad 
      de Medicina, Universidad Autonoma de Madrid, Madrid, Spain.
FAU - Duarte, Pablo
AU  - Duarte P
AD  - Instituto de Quimica Medica, Consejo Superior de Investigaciones Cientificas 
      (IQM-CSIC), Madrid, Spain.
AD  - Instituto Teofilo Hernando y Departamento de Farmacologia y Terapeutica, Facultad 
      de Medicina, Universidad Autonoma de Madrid, Madrid, Spain.
FAU - Dauden, Esteban
AU  - Dauden E
AD  - Instituto Teofilo Hernando y Departamento de Farmacologia y Terapeutica, Facultad 
      de Medicina, Universidad Autonoma de Madrid, Madrid, Spain.
FAU - Cuadrado, Antonio
AU  - Cuadrado A
AD  - Departmento de Bioquimica, Centro de Investigacion Biomedica en Red Sobre 
      Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigacion Sanitaria 
      La Paz (IdiPaz), Instituto de Investigaciones Biomedicas 'Alberto Sols' 
      UAM-CSIC, Facultad de Medicina, Universidad Autonoma de Madrid, Madrid, Spain.
FAU - Rodriguez-Franco, Maria Isabel
AU  - Rodriguez-Franco MI
AUID- ORCID: 0000-0002-6500-792X
AD  - Instituto de Quimica Medica, Consejo Superior de Investigaciones Cientificas 
      (IQM-CSIC), Madrid, Spain.
FAU - Lopez, Manuela G
AU  - Lopez MG
AD  - Instituto de Investigacion Sanitaria La Princesa, Hospital Universitario de la 
      Princesa, Madrid, Spain.
AD  - Instituto Teofilo Hernando y Departamento de Farmacologia y Terapeutica, Facultad 
      de Medicina, Universidad Autonoma de Madrid, Madrid, Spain.
FAU - Leon, Rafael
AU  - Leon R
AUID- ORCID: 0000-0003-4017-5756
AD  - Instituto de Quimica Medica, Consejo Superior de Investigaciones Cientificas 
      (IQM-CSIC), Madrid, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20220910
PL  - United States
TA  - Med Res Rev
JT  - Medicinal research reviews
JID - 8103150
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
SB  - IM
MH  - Humans
MH  - Inflammation/drug therapy
MH  - *Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors/metabolism
MH  - *Neurodegenerative Diseases
MH  - *NF-E2-Related Factor 2/antagonists & inhibitors/metabolism
MH  - Oxidative Stress
PMC - PMC10087726
OTO - NOTNLM
OT  - KEAP1-NRF2 protein-protein interaction inhibitors
OT  - NRF2
OT  - NRF2-ARE pathway therapeutic potential
OT  - chronic diseases
OT  - phase II antioxidant response
COIS- The authors declare no conflict of interest.
EDAT- 2022/09/11 06:00
MHDA- 2022/12/07 06:00
PMCR- 2023/04/11
CRDT- 2022/09/10 03:32
PHST- 2022/06/27 00:00 [revised]
PHST- 2021/11/09 00:00 [received]
PHST- 2022/08/18 00:00 [accepted]
PHST- 2022/09/11 06:00 [pubmed]
PHST- 2022/12/07 06:00 [medline]
PHST- 2022/09/10 03:32 [entrez]
PHST- 2023/04/11 00:00 [pmc-release]
AID - MED21925 [pii]
AID - 10.1002/med.21925 [doi]
PST - ppublish
SO  - Med Res Rev. 2023 Jan;43(1):237-287. doi: 10.1002/med.21925. Epub 2022 Sep 10.