Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review

Figures & data

Figure 1 Schematic overview of the Nrf2/Keap1 signaling pathway in homeostatic and stress conditions.

Abbreviations: ARE, antioxidant response element; CuI3, Cullin-3; Maf, musculoaponeurotic fibrosarcoma; RNS, reactive nitrogen species; ROS, reactive oxygen species; Ub, ubiquitination.

Figure 2 A surface presentation of the Kelch domain (gray) with two bound peptides from crystal structures: 2FLU (red)¹⁸ and 3ZGC (yellow).¹⁹

Table 1 The origin and mechanisms of the Nrf2 activation in different cancer types

Mechanisms of Nrf2 activation	Type of cancer	Change/cause (representative examples)	Reference
Somatic mutations in Keap1	Lung, AD	G430C, R415G	^Citation41, ^Citation42
		E244K, E242K, W591L	^Citation43
	Lung, NSCC	G333C	^Citation44
	Lung, SQ	S45F, V42A, R320	^Citation43
	Gastric, AD	F280L, Q82H, S233N	^Citation43
	Colorectal, AD	T330I, V660M, R234W	^Citation43
	HCC	D236Y, L342M, N183S	^Citation43
	Breast cancer	D256G	^Citation43
		C23Y	^Citation45
	Prostate, AD	D357N	^Citation43
		Y255H, T314M	^Citation46
	Gallbladder, AD	G379D, S338L	^Citation47
	Liver, CCC	W554X, C249Y	^Citation47
	Epithelial ovarian cancer, CC	F107L, A159T and A188V, E611K, P412S	^Citation48
Somatic mutations in Nrf2	Lung, AD	E79Q	^Citation49
	Lung, NSCC	D77V, E79K	^Citation49
	Lung, SQ	E79K, T80R, E82G, etc	^Citation49, ^Citation41
		D77A, E79K or Q, G81D, E82Q, etc	^Citation50
	Head and neck	Q75H, T80I, D29G	^Citation49
	LCNEC	W24C	^Citation49
	Larynx, SQ	D77N, E79G, D29H	^Citation50
	Skin, SQ	G31A	^Citation50
	Esophagus, SQ	T80K, G81V, E82L, D27Y	^Citation50
		D77V or G, E78K, E79K, T80K, G81D	^Citation51
	Cervical, SQ	E79Q	^Citation51
	Malignant melanoma	L30F	^Citation51
Epigenetic silencing of Keap1 gene	Lung	Hypermethylation of the Keap1 gene	^Citation52
	Colorectal	Hypermethylation of the Keap1 promoter region (CpG island hypermethylation)	^Citation53
	Prostate	CpG island hypermethylation	^Citation46
Accumulation of Keap1-interacting proteins	HCC	Phosphorylation of the autophagy-adaptor protein p62	^Citation54
		p62 accumulation	^Citation55
Cysteine modification of Keap1	Type 2 papillary renal cell carcinoma	Fumarate accumulation due to mutation in fumarate hydratase	^Citation56

Abbreviations: AD, adenocarcinoma; CC, clear cell carcinoma; CCC, cholangiocellular carcinoma; HCC, hepatocellular carcinoma; LCNEC, large-cell neuroendocrine carcinoma; NSCC, non-small-cell carcinoma; SQ, squamous carcinoma.

Figure 3 Different strategies used for the design of Nrf2/Keap1 signaling pathway modulators.

Abbreviations: CAPE, caffeic acid phenethyl ester; D3T, 3H-1,2-dithiole-3-thione; FIDA, fluorescence intensity distribution analysis; FITC, fluorescein isothiocyanate; HTS, high-throughput screening; SPR, surface plasmon resonance.

Figure 4 A surface presentation of the Kelch domain (gray) in complex with inhibitors of the Keap1-Nrf2 interactions from crystal structures: (1S,2R)-2-{[(1S)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclohexanecarboxylic acid (13)⁷⁷ (green, PDB ID: 4L7B), 2-({5-[(2,4-dimethylphenyl) sulfonyl]-6-oxo-1,6-dihydropyrimidin-2-yl}sulfanyl)-N-[2-(trifluoromethyl)phenyl]acetamide (14)⁶⁷ (cyan, PDB ID: 4IN4), 2,2′-(naphthalene-1,4-diylbis(((4-methoxyphenyl) sulfonyl)azanediyl))diacetamide⁸¹ (yellow, PDB ID: 4XMB), N,N′-[2-(2-oxopropyl)naphthalene-1,4-diyl]bis(4-ethoxybenzenesulfonamide) (51)⁸² (light blue, PDB ID: 4ZY3), (3S)-1-(4-{[(2,3,5,6-tetramethylphenyl)sulfonyl]amino}naphthalen-1-yl)pyrrolidine-3-carboxylic acid⁸³ (orange, PDB ID: 5CGJ), and 3-(4-chlorophenyl)propanoic acid⁷⁴ (blue, PDB ID: 5FNQ).

Abbreviation: PBD, Protein Data Bank.

Figure 5 Natural and synthetic Nrf2 modulators as potential cancer chemopreventive and therapeutic agents.

LoSCLiXHenzlMTBeamerLJHanninkMStructure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signalingEmbo J200625153605361716888629

 PubMed Web of Science ®Google Scholar

HörerSReinertDOstmannKHoevelsYNarHCrystal-contact engineering to obtain a crystal form of the Kelch domain of human Keap1 suitable for ligand-soaking experimentsActa Crystallogr Sect F Struct Biol Cryst Commun2013696592596

 PubMedGoogle Scholar

PadmanabhanBTongKIOhtaTStructural basis for defects of Keap1 activity provoked by its point mutations in lung cancerMol Cell200621568970016507366

 PubMed Web of Science ®Google Scholar

OhtaTIijimaKMiyamotoMLoss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growthCancer Res20086851303130918316592

 PubMed Web of Science ®Google Scholar

YooNJKimHRKimYRAnCHLeeSHSomatic mutations of the KEAP1 gene in common solid cancersHistopathology201260694395222348534

 PubMed Web of Science ®Google Scholar

SinghAMisraVThimmulappaRKDysfunctional KEAP1–NRF2 interaction in non-small-cell lung cancerPLoS Med2006310e42017020408

 PubMed Web of Science ®Google Scholar

NioiPNguyenTA mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activityBiochem Biophys Res Commun2007362481682117822677

 PubMed Web of Science ®Google Scholar

ZhangPSinghAYegnasubramanianSLoss of Keap1 function in prostate cancer cells causes chemo- and radio-resistance and promotes tumor growthMol Cancer Ther20109233620124447

 PubMed Web of Science ®Google Scholar

ShibataTKokubuAGotohMGenetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancerGastroenterology200813541358136818692501

 PubMed Web of Science ®Google Scholar

KonstantinopoulosPASpentzosDFountzilasEKeap1 mutations and Nrf2 pathway activation in epithelial ovarian cancerCancer Res201171155081508921676886

 PubMed Web of Science ®Google Scholar

ShibataTOhtaTTongKICancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancyProc Natl Acad Sci U S A200810536135681357318757741

 PubMed Web of Science ®Google Scholar

KimYROhJEKimMSOncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skinJ Pathol2010220444645119967722

 PubMed Web of Science ®Google Scholar

ShibataTKokubuASaitoSNRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancerNeoplasia201113986487321969819

 PubMed Web of Science ®Google Scholar

WangRAnJJiFHypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissuesBiochem Biophys Res Commun2008373115115418555005

 PubMed Web of Science ®Google Scholar

HanadaNTakahataTZhouQMethylation of the KEAP1 gene promoter region in human colorectal cancerBMC Cancer20121216622325485

 PubMed Web of Science ®Google Scholar

IchimuraYWaguriSSouYSPhosphorylation of p62 Activates the Keap1-Nrf2 Pathway during Selective AutophagyMol Cell201351561863124011591

 PubMed Web of Science ®Google Scholar

InamiYWaguriSSakamotoAPersistent activation of Nrf2 through p62 in hepatocellular carcinoma cellsJ Cell Biol2011193227528421482715

 PubMed Web of Science ®Google Scholar

OoiAWongJ-CPetilloDAn antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinomaCancer Cell201120451152322014576

 PubMed Web of Science ®Google Scholar

JnoffEAlbrechtCBarkerJJBinding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complexChemMedChem20149469970524504667

 PubMed Web of Science ®Google Scholar

MarcotteDZengWHusJ-CSmall molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanismBioorg Med Chem201321144011401923647822

 PubMed Web of Science ®Google Scholar

JainADPottetiHRichardsonBGProbing the structural requirements of non-electrophilic naphthalene-based Nrf2 activatorsEur J Med Chem201510325226826363505

 PubMed Web of Science ®Google Scholar

SaitoTIchimuraYTaguchiKp62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogrammingNat Commun201671203027345495

 PubMed Web of Science ®Google Scholar

WinkelAFEngelCKMargerieDCharacterization of RA839, a noncovalent small molecule binder to Keap1 and selective activator of Nrf2 signalingJ Biol Chem201529047284462845526459563

 PubMed Web of Science ®Google Scholar

DaviesTGWixtedWECoyleJEMonoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear factor erythroid 2-related factor 2 (KEAP1:NRF2) protein–protein interaction with high cell potency identified by fragment-based discoveryJ Med Chem20165983991400627031670

 PubMed Web of Science ®Google Scholar