PMID- 32435379
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210514
IS  - 1948-5875 (Print)
IS  - 1948-5875 (Electronic)
IS  - 1948-5875 (Linking)
VI  - 11
IP  - 5
DP  - 2020 May 14
TI  - Combined Peptide and Small-Molecule Approach toward Nonacidic THIQ Inhibitors of 
      the KEAP1/NRF2 Interaction.
PG  - 740-746
LID - 10.1021/acsmedchemlett.9b00594 [doi]
AB  - The NRF2-ARE pathway is an intrinsic mechanism of defense against oxidative 
      stress. Inhibition of the interaction between NRF2 and its main negative 
      regulator KEAP1 is an attractive strategy toward neuroprotective agents. We 
      report here the identification of nonacidic tetrahydroisoquinolines (THIQs) that 
      inhibit the KEAP1/NRF2 protein-protein interaction. Peptide SAR at one residue is 
      utilized as a tool to probe structural changes within a specific pocket of the 
      KEAP1 binding site. We used structural information from peptide screening at the 
      P2 pocket, noncovalent small-molecules inhibitors, and the outcome from an 
      explorative SAR at position 5 of THIQs to identify a series of neutral THIQ 
      analogs that bind to KEAP1 in the low micromolar range. These analogs establish 
      new H-bond interactions at the P3 and P2 pockets allowing the replacement of the 
      carboxylic acid functionality by a neutral primary carboxamide. X-ray 
      crystallographic studies reveal the novel binding mode of these molecules to 
      KEAP1.
CI  - Copyright (c) 2020 American Chemical Society.
FAU - Ontoria, Jesus M
AU  - Ontoria JM
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
FAU - Biancofiore, Ilaria
AU  - Biancofiore I
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
FAU - Fezzardi, Paola
AU  - Fezzardi P
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
FAU - Ferrigno, Federica
AU  - Ferrigno F
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
FAU - Torrente, Esther
AU  - Torrente E
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
FAU - Colarusso, Stefania
AU  - Colarusso S
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
FAU - Bianchi, Elisabetta
AU  - Bianchi E
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
FAU - Andreini, Matteo
AU  - Andreini M
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
FAU - Patsilinakos, Alexandros
AU  - Patsilinakos A
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
FAU - Kempf, Georg
AU  - Kempf G
AD  - Proteros Biostructures GmbH, Bunsenstrasse 7 a, 82152 Planegg, Germany.
FAU - Augustin, Martin
AU  - Augustin M
AD  - Proteros Biostructures GmbH, Bunsenstrasse 7 a, 82152 Planegg, Germany.
FAU - Steinbacher, Stefan
AU  - Steinbacher S
AD  - Proteros Biostructures GmbH, Bunsenstrasse 7 a, 82152 Planegg, Germany.
FAU - Summa, Vincenzo
AU  - Summa V
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
FAU - Pacifici, Robert
AU  - Pacifici R
AD  - CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 
      90045, United States.
FAU - Munoz-Sanjuan, Ignacio
AU  - Munoz-Sanjuan I
AD  - CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 
      90045, United States.
FAU - Park, Larry
AU  - Park L
AD  - CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 
      90045, United States.
FAU - Bresciani, Alberto
AU  - Bresciani A
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
FAU - Dominguez, Celia
AU  - Dominguez C
AD  - CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 
      90045, United States.
FAU - Sherman, Leticia Toledo
AU  - Sherman LT
AD  - CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 
      90045, United States.
FAU - Harper, Steven
AU  - Harper S
AD  - IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
LA  - eng
PT  - Journal Article
DEP - 20200403
PL  - United States
TA  - ACS Med Chem Lett
JT  - ACS medicinal chemistry letters
JID - 101521073
PMC - PMC7236277
COIS- The authors declare no competing financial interest.
EDAT- 2020/05/22 06:00
MHDA- 2020/05/22 06:01
PMCR- 2021/05/14
CRDT- 2020/05/22 06:00
PHST- 2019/12/11 00:00 [received]
PHST- 2020/04/03 00:00 [accepted]
PHST- 2020/05/22 06:00 [entrez]
PHST- 2020/05/22 06:00 [pubmed]
PHST- 2020/05/22 06:01 [medline]
PHST- 2021/05/14 00:00 [pmc-release]
AID - 10.1021/acsmedchemlett.9b00594 [doi]
PST - epublish
SO  - ACS Med Chem Lett. 2020 Apr 3;11(5):740-746. doi: 10.1021/acsmedchemlett.9b00594. 
      eCollection 2020 May 14.