2. Academic Validation
  3. Optimization of the C2 substituents on the 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acid scaffold for better inhibition of Keap1-Nrf2 protein-protein interaction

Optimization of the C2 substituents on the 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acid scaffold for better inhibition of Keap1-Nrf2 protein-protein interaction

  • Eur J Med Chem. 2023 Apr 5;252:115302. doi: 10.1016/j.ejmech.2023.115302.
Dhulfiqar Ali Abed 1,  Ahmed R Ali 1,  Sumi Lee 1,  Mai-Uyen Nguyen 2,  Michael P Verzi 3,  Longqin Hu 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA.
  • 2 Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Life Sciences Building Rutgers University, 145 Bevier Road Piscataway, NJ, 08854, USA.
  • 3 Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Life Sciences Building Rutgers University, 145 Bevier Road Piscataway, NJ, 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.
  • 4 Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. Electronic address: LongHu@pharmacy.rutgers.edu.
PMID: 36989811 DOI: 10.1016/j.ejmech.2023.115302
Abstract

Direct inhibition of the protein-protein interaction (PPI) between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) reduces the ubiquitination and subsequent degradation of Nrf2, leading to Nrf2 accumulation in the cytosol and the nuclear translocation of Nrf2. Once inside the nucleus, Nrf2 binds to and activates the expression of antioxidant response element (ARE) genes involved in redox homeostasis and detoxification. Herein, we report a series of 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acid analogs with varying C2 substituents to explore the structure-activity relationships at this position of the central naphthalene core. The Keap1-binding activities were first screened with a fluorescence polarization (FP) assay followed by further evaluation of the more potent compounds using a more sensitive time-resolved fluorescence energy transfer (TR-FRET) assay. It was found that compound 24a with C2-phthalimidopropyl group was the most potent in this series showing an IC50 of 2.5 nM in the TR-FRET assay with a Ki value in the subnanomolar range. Our docking study indicated that the C2-phthalimidopropyl group in compound 24a provided an extra hydrogen bonding interaction with the key residue Arg415 that may be responsible for the observed boost in binding affinity. In addition, compounds 12b, 15, and 24a were shown to activate the Nrf2 signaling pathway in NCM460D cells resulting in elevated mRNA levels of GSTM3, HMOX1 and NQO1 by 2.4-11.7 fold at 100 μM as compared to the vehicle control.

Keywords

C-2 naphthalene derivatives; Fluorescence polarization; Keap1; Keap1-Nrf2 interaction; Nrf2; Protein-protein interaction inhibitor; Structure-activity relationship; TR-FRET.

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