Design, synthesis and evaluation of novel small molecules acting as Keap1-Nrf2 protein-protein interaction inhibitors

References

• Yamamoto M, Kensler TW, Motohashi H. The keap1-nrf2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev. 2018;98(3):1169–1203.
   PubMed Web of Science ®Google Scholar
• Yang S, Lian G. Ros and diseases: role in metabolism and energy supply. Mol Cell Biochem. 2020;467(1–2):1–12.
   PubMed Web of Science ®Google Scholar
• Dickinson BC, Chang CJ. Chemistry and biology of reactive oxygen species in signaling or stress responses. Nat Chem Biol. 2011;7(8):504–511.
   PubMed Web of Science ®Google Scholar
• Tonelli C, Chio C II, Tuveson DA. Transcriptional regulation by nrf2. Antioxid Redox Signal. 2018;29(17):1727–1745.
   PubMed Web of Science ®Google Scholar
• Sajadimajd S, Khazaei M. Oxidative stress and cancer: the role of nrf2. Curr Cancer Drug Targets. 2018;18(6):538–557.
   PubMed Web of Science ®Google Scholar
• Baird L, Yamamoto M. The molecular mechanisms regulating the keap1-nrf2 pathway. Mol Cell Biol. 2020;40(13):e00099–00020.
   PubMed Web of Science ®Google Scholar
• Zhou HS, Hu LB, Zhang H, Shan WX, Wang Y, Li X, Liu T, Zhao J, You QD, Jiang ZY. Design, synthesis, and structure-activity relationships of indoline-based kelch-like ech-associated protein 1-nuclear factor (erythroid-derived 2)-like 2 (keap1-nrf2) protein-protein interaction inhibitors. J Med Chem. 2020;63(19):11149–11168.
   PubMed Web of Science ®Google Scholar
• Houghton CA, Fassett RG, Coombes JS. Sulforaphane and other nutrigenomic nrf2 activators: can the clinician’s expectation be matched by the reality? Oxid Med Cell Longev. 2016;2016:7857186.
   PubMed Web of Science ®Google Scholar
• Fu CY, Chen J, Lu XY, Zheng MZ, Wang LL, Shen YL, Chen YY. Dimethyl fumarate attenuates lipopolysaccharide-induced mitochondrial injury by activating nrf2 pathway in cardiomyocytes. Life Sci. 2019;235:116863.
   PubMed Web of Science ®Google Scholar
• Marcotte D, Zeng W, Hus JC, McKenzie A, Hession C, Jin P, Bergeron C, Lugovskoy A, Enyedy I, Cuervo H, et al. Small molecules inhibit the interaction of nrf2 and the keap1 kelch domain through a non-covalent mechanism. Bioorg Med Chem. 2013;21(14):4011–4019.
   PubMed Web of Science ®Google Scholar
• Hu L, Magesh S, Chen L, Wang L, Lewis TA, Chen Y, Khodier C, Inoyama D, Beamer LJ, Emge TJ, et al. Discovery of a small-molecule inhibitor and cellular probe of keap1-nrf2 protein-protein interaction. Bioorg Med Chem Lett. 2013;23(10):3039–3043.
   PubMed Web of Science ®Google Scholar
• Jiang CS, Zhuang CL, Zhu K, Zhang J, Muehlmann LA, Figueiró Longo JP, Azevedo RB, Zhang W, Meng N, Zhang H. Identification of a novel small-molecule keap1-nrf2 ppi inhibitor with cytoprotective effects on lps-induced cardiomyopathy. J Enzyme Inhib Med Chem. 2018;33(1):833–841.
   PubMed Web of Science ®Google Scholar
• Lazzara PR, David BP, Ankireddy A, Richardson BG, Dye K, Ratia KM, Reddy SP, Moore TW. Isoquinoline kelch-like ech-associated protein 1-nuclear factor (erythroid-derived 2)-like 2 (keap1-nrf2) inhibitors with high metabolic stability. J Med Chem. 2020;63(12):6547–6560.
   PubMed Web of Science ®Google Scholar
• Cosimelli B, Greco G, Laneri S, Novellino E, Sacchi A, Amendola G, Cosconati S, Bortolozzi R, Viola G. Identification of novel indole derivatives acting as inhibitors of the keap1-nrf2 interaction. J Enzyme Inhib Med Chem. 2019;34(1):1152–1157.
   PubMed Web of Science ®Google Scholar
• Bertrand HC, Schaap M, Baird L, Georgakopoulos ND, Fowkes A, Thiollier C, Kachi H, Dinkova-Kostova AT, Wells G. Design, synthesis, and evaluation of triazole derivatives that induce nrf2 dependent gene products and inhibit the keap1-nrf2 protein-protein interaction. J Med Chem. 2015;58(18):7186–7194.
   PubMed Web of Science ®Google Scholar
• Abed DA, Lee S, Hu L. Discovery of disubstituted xylylene derivatives as small molecule direct inhibitors of keap1-nrf2 protein-protein interaction. Bioorg Med Chem. 2020;28(6):115343.
   PubMed Web of Science ®Google Scholar
• Begnini F, Geschwindner S, Johansson P, Wissler L, Lewis RJ, Danelius E, Luttens A, Matricon P, Carlsson J, Lenders S, et al. Importance of binding site hydration and flexibility revealed when optimizing a macrocyclic inhibitor of the keap1-nrf2 protein-protein interaction. J Med Chem. 2022;65(4):3473–3517.
   PubMed Web of Science ®Google Scholar
• Lee S, Abed DA, Nguyen MU, Verzi MP, Hu L. 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;237:114380.
   PubMed Web of Science ®Google Scholar
• Georgakopoulos N, Talapatra S, Dikovskaya D, Dayalan Naidu S, Higgins M, Gatliff J, Ayhan A, Nikoloudaki R, Schaap M, Valko K, et al. Phenyl bis-sulfonamide keap1-nrf2 protein-protein interaction inhibitors with an alternative binding mode. J Med Chem. 2022;65(10):7380–7398.
   PubMedGoogle Scholar
• Hsu KH, Su BH, Tu YS, Lin OA, Tseng YJ. Mutagenicity in a molecule: Identification of core structural features of mutagenicity using a scaffold analysis. PLOS One. 2016;11(2):e0148900.
   PubMed Web of Science ®Google Scholar
• Ying Y, Ye JJ, Sun L, Wang P, Wang H. X. Phloretin prevents diabetic cardiomyopathy by dissociating keap1/nrf2 complex and inhibiting oxidative stress. Front Endocrinol. 2018;9:774.
   Google Scholar
• Jiang ZY, Lu MC, Xu LL, Yang TT, Xi MY, Xu XL, Guo XK, Zhang XJ, You QD, Sun HP. Discovery of potent keap1-nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J Med Chem. 2014;57(6):2736–2745.
   PubMed Web of Science ®Google Scholar
• Hur W, Gray NS. Small molecule modulators of antioxidant response pathway. Curr Opin Chem Biol. 2011;15(1):162–173.
   PubMed Web of Science ®Google Scholar
• Magesh S, Chen Y, Hu L. Small molecule modulators of keap1-nrf2-are pathway as potential preventive and therapeutic agents. Med Res Rev. 2012;32(4):687–726.
   PubMed Web of Science ®Google Scholar
• Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA. Nrf2, a multi-organ protector? Faseb J. 2005;19(9):1061–1066.
   PubMed Web of Science ®Google Scholar
• Meng N, Tang H, Zhang H, Jiang C, Su L, Min X, Zhang W, Zhang H, Miao Z, Zhang W, et al. Fragment-growing guided design of keap1-nrf2 protein-protein interaction inhibitors for targeting myocarditis. Free Radic Biol Med. 2018;117:228–237.
   PubMed Web of Science ®Google Scholar
• Cheng N, Liang Y, Du X, Ye RD. Serum amyloid a promotes lps clearance and suppresses lps-induced inflammation and tissue injury. EMBO Rep. 2018;19(10):e45517.
   PubMed Web of Science ®Google Scholar
• Lakshmikanth CL, Jacob SP, Chaithra VH, de Castro-Faria-Neto HC, Marathe GK. Sepsis: in search of cure. Inflamm Res. 2016;65(8):587–602.
   PubMed Web of Science ®Google Scholar
• Baell JB, Holloway GA. New substructure filters for removal of pan assay interference compounds (pains) from screening libraries and for their exclusion in bioassays. J Med Chem. 2010;53(7):2719–2740.
   PubMed Web of Science ®Google Scholar
• Inoyama D, Chen Y, Huang X, Beamer LJ, Kong AN, Hu L. Optimization of fluorescently labeled nrf2 peptide probes and the development of a fluorescence polarization assay for the discovery of inhibitors of keap1-nrf2 interaction. J Biomol Screen. 2012;17(4):435–447.
   PubMedGoogle Scholar
• Ontoria JM, Biancofiore I, Fezzardi P, Ferrigno F, Torrente E, Colarusso S, Bianchi E, Andreini M, Patsilinakos A, Kempf G, et al. Combined peptide and small-molecule approach toward nonacidic thiq inhibitors of the keap1/nrf2 interaction. ACS Med Chem Lett. 2020;11(5):740–746.
   PubMed Web of Science ®Google Scholar
• Daina A, Michielin O, Zoete V. Swissadme: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717.
   PubMed Web of Science ®Google Scholar