2. Academic Validation
  3. Structure-activity relationships of 1,4-bis(arylsulfonamido)-benzene or naphthalene-N,N'-diacetic acids with varying C2-substituents as inhibitors of Keap1-Nrf2 protein-protein interaction

Structure-activity relationships of 1,4-bis(arylsulfonamido)-benzene or naphthalene-N,N'-diacetic acids with varying C2-substituents as inhibitors of Keap1-Nrf2 protein-protein interaction

  • Eur J Med Chem. 2022 Jul 5;237:114380. doi: 10.1016/j.ejmech.2022.114380.
Sumi Lee 1,  Dhulfiqar Ali Abed 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, United States.
  • 2 Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Life Sciences Building, 145 Bevier Road, Piscataway, NJ, 08854, United States.
  • 3 Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Life Sciences Building, 145 Bevier Road, Piscataway, NJ, 08854, United States; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, United States.
  • 4 Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, United States; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, United States. Electronic address: LongHu@pharmacy.rutgers.edu.
PMID: 35462166 DOI: 10.1016/j.ejmech.2022.114380
Abstract

The Keap1-Nrf2-ARE pathway plays an important role in responding to oxidative stress and maintaining the redox homeostasis. Small molecule inhibitors targeting directly the Keap1-Nrf2 protein-protein interaction (PPI) can potentially be developed into effective preventive and therapeutic agents for numerous chronic inflammatory diseases. To improve the drug-like properties and inhibitory potency of these inhibitors, a series of 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N'-diacetic acids with varying substituents at C-2 position of the benzene or naphthalene core were designed and synthesized. Among them, compound 12d with 2-(4-fluorobenzyloxy) group was the most potent direct inhibitor of Keap1-Nrf2 PPI with an IC50 of 64.5 nM in the fluorescent polarization (FP) assay and 14.2 nM in a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Moreover, cell-based biological assay showed that 12d significantly increased the mRNA levels of Nrf2 downstream genes, GSTM3, HMOX2 and NQO1, through Nrf2 activation. The discovery of the new scaffolds possessing diverse O-linked fragments at the C2 position offers opportunities to further modify the chemical structures of Keap1-Nrf2 PPI inhibitors to improve their pharmacokinetic, efficacy and safety profiles.

Keywords

Keap1; Keap1-Nrf2 interaction; Nrf2; Oxidative stress; Protein-protein interaction inhibitor; Structural diversity; Structure-activity relationship.

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