1. Combined Peptide and Small-Molecule Approach toward Nonacidic THIQ Inhibitors of the KEAP1/NRF2 Interaction
- Author
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Georg Kempf, Ignacio Munoz-Sanjuan, Alexandros Patsilinakos, Matteo Andreini, Stefania Colarusso, Vincenzo Summa, Jesus Maria Ontoria Ontoria, Federica Ferrigno, Paola Fezzardi, Steven J. Harper, Leticia Toledo Sherman, Stefan Steinbacher, Ilaria Biancofiore, Esther Torrente, Martin Augustin, Elisabetta Bianchi, Larry Park, Alberto Bresciani, Robert Pacifici, Celia Dominguez, 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., and Harper, S.
- Subjects
chemistry.chemical_classification ,Chemistry ,Tetrahydroisoquinoline ,Organic Chemistry ,Huntington's disease ,Peptide ,respiratory system ,digestive system ,environment and public health ,Biochemistry ,KEAP1 ,Small molecule ,Keap1 nrf2 ,NRF2 ,Protein–protein interaction ,Negative regulator ,protein-protein interaction ,chemistry.chemical_compound ,THIQ ,Drug Discovery ,Biophysics ,medicine ,tetrahydroisoquinoline ,medicine.drug - Abstract
[Image: see text] 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.
- Published
- 2020
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