6SP4

KEAP1 IN COMPLEX WITH COMPOUND 23

Summary for 6SP4

• Entry DOI: 10.2210/pdb6sp4/pdb
• Descriptor: Kelch-like ECH-associated protein 1, (1~{S},2~{R})-2-[[(1~{S})-1-[[1,3-bis(oxidanylidene)isoindol-2-yl]methyl]-5-(2-hydroxyethyloxy)-3,4-dihydro-1~{H}-isoquinolin-2-yl]carbonyl]cyclobutane-1-carboxamide (3 entities in total)
• Functional Keywords: nrf2, keap1, protein-protein interactions, huntingtons disease, tetrahydroisoquinoline, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 194575.69

Authors

Ontoria, J.M.,Biancofiore, I.,Fezzardi, P.,Torrente de Haro, E.,Colarusso, S.,Bianchi, E.,Andreini, M.,Patsilinakos, A.,Summa, V.,Pacifici, R.,Munoz-Sanjuan, I.,Park, L.,Bresciani, A.,Dominguez, C.,Toledo-Sherman, L.,Harper, S. (deposition date: 2019-08-30, release date: 2020-06-03, Last modification date: 2024-11-13)

Primary citation

Ontoria, J.M.,Biancofiore, I.,Fezzardi, P.,Ferrigno, F.,Torrente, E.,Colarusso, S.,Bianchi, E.,Andreini, M.,Patsilinakos, A.,Kempf, G.,Augustin, M.,Steinbacher, S.,Summa, V.,Pacifici, R.,Munoz-Sanjuan, I.,Park, L.,Bresciani, A.,Dominguez, C.,Sherman, L.T.,Harper, S.
Combined Peptide and Small-Molecule Approach toward Nonacidic THIQ Inhibitors of the KEAP1/NRF2 Interaction.
Acs Med.Chem.Lett., 11:740-746, 2020

PubMed Abstract: 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.

PubMed: 32435379
DOI: 10.1021/acsmedchemlett.9b00594

Experimental method

X-RAY DIFFRACTION (2.59 Å)