Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development

Table 1

Selected electrophilic activators of NRF2 under clinical development.

Compound	Type	Mechanism of action	Disease	Clinical trial	ClinicalTrials.gov identifier
Bardoxolone-methyl (CDDO-Me)	Synthetic triterpenoids	Electrophilic modification of KEAP1-Cys-151	Diabetic nephropathy	Phase II	NCT00811889
			IgA nephropathy; CKD associated with type 1 diabetes; Focal segmental glomerulosclerosis; Autosomal dominant polycystic kidney	Phase II	NCT03366337
			Chronic kidney disease; Type 2 diabetes; Diabetic nephropathy	Phase III	NCT01351675
			Liver disease	Phase I/II	NCT00550849
			Hepatic impairment; Healthy	Phase I	NCT01563562
			Advanced solid tumors lymphoid malignancies	Phase I	NCT00529438; NCT00508807
			Alport syndrome	Phase II/III cardinal	NCT03019185
			Pulmonary hypertension	Phase III RANGER	NCT03068130
			Pulmonary arterial hypertension	Phase III	NCT02657356
			Renal insufficiency, chronic; Diabetes mellitus, type 2	Phase II	NCT01053936
RTA-408 (omaveloxolone)	Synthetic triterpenoids	Electrophilic modification of KEAP1-Cys-151	Mitochondrial myopathy	Phase II	NCT02255422
			Friedreich’s ataxia	Phase II	NCT02255435
			Inflammation and pain following ocular surgery	Phase II	NCT02065375
			Corneal endothelial cell loss; Ocular pain; Ocular inflammation; Cataract surgery	Phase II	NCT02128113
			Melanoma	Phase I/II	NCT02259231
			Breast cancer	Phase II	NCT02142959
Dimethyl fumarate	Fumaric acid ester	Electrophilic modification of KEAP1-Cys-151	Multiple sclerosis	Approved
			Psoriasis	Approved
			Rheumatoid arthritis	Phase II	NCT00810836
			Adult brain glioblastoma	Phase I	NCT02337426
			Cutaneous T cell lymphoma	Phase II	NCT02546440
			Obstructive sleep apnea	Phase II	NCT02438137
			Chronic lymphocytic leukemia; Small lymphocytic lymphoma	Phase I	NCT02784834
ALKS-8700	Fumaric acid ester (MMF-derivate)	Electrophilic modification of KEAP1-Cys-151	Multiple sclerosis	Phase III	NCT02634307
Oltipraz	Organosulfur compound	Electrophilic modification of KEAP1-Cys-151	Nonalcoholic steatohepatitis	Phase III	NCT02068339
			Schistosomiasis	Approved
			Lung cancer	Phase I	NCT00006457
Ursodiol	Biliary acid	Electrophilic modification of KEAP1-Cys-151	Cholestasis	Phase II/III	NCT00846963
			Diarrhea	Phase IV	NCT02748616
			Cholelithiasis	Phase III	NCT02721862
			Primary biliary cirrhosis	Phase IV	NCT01510860
			Barrett esophagus; Low-grade dysplasia	Phase II	NCT01097304
			Chronic hepatitis C	Phase III	NCT00200343
			Type 2 diabetes mellitus	Phase II	NCT02033876
Sulforaphane	Isothiocyanate	Electrophilic modification of KEAP1-Cys-151	Schizophrenia	Phase II/III	NCT02880462
				Phase II	NCT02810964
				Phase II	NCT01716858
			COPD	Phase II	NCT01335971
			Atopic asthmatics	Phase I	NCT01845493
			Autism spectrum disorder	Phase II	NCT01474993
				Phase II	NCT02909959
				Phase II	NCT02677051
				Phase II	NCT02654743
				Phase I/II	NCT02561481
			Healthy	Phase I	NCT01008826
				Phase I	NCT02023931
			Melanoma	Phase I	NCT01568996
			Asthma	Phase I	NCT01845493
				Phase I/II	NCT01183923
			Prostate cancer	Phase II	NCT01228084
			Breast cancer	Phase II	NCT00843167
			Lung cancer	Phase II	NCT03232138
			Environmental carcinogenesis	Phase II	NCT01437501
			Alcohol sensitivity	Phase II	NCT01845220
			Aging	Phase II	NCT03126539
			Rhinitis, allergic	Phase II	NCT02885025
			Helicobacter pylori infection	Phase IV	NCT03220542
			Diabetes mellitus, noninsulin-dependent	Phase II	NCT02801448
Sulforadex (SFX-01)	Sulforaphane/alpha-cyclodextrin complex	Electrophilic modification of KEAP1-Cys-151	Subarachnoid haemorrhage	Phase II	NCT02614742
			Breast neoplasm	Phase I/II	NCT02970682
			Prostate cancer	Phase I	NCT02055716; NCT01948362
ITH12674	Melatonin-sulforaphane hybrid	Electrophilic modification of KEAP1-Cys-151	Brain ischemia	Preclinical PK	No clinical trials available
Curcumin	Stilbene	Electrophilic modification of KEAP1-Cys-151	Type 2 diabetes; Prediabetes; Insulin resistance; Cardiovascular risk	Phase IV	NCT01052025
			Schizophrenia; Cognition; Psychosis	Phase I/II	NCT02104752
			Acute kidney injury; Abdominal aortic aneurysm	Phase II/III	NCT01225094
			Chronic kidney diseases; Diabetes mellitus, type 2; Polymorphism	Phase II/III	NCT03262363
			Alzheimer’s disease	Phase I/II	NCT00164749
			Neoplasms	Phase II	NCT02944578
			Crohn’s disease	Phase III	NCT02255370
			Chronic schizophrenia	Phase IV	NCT02298985
			Mild cognitive impairment	Phase II	NCT01811381
			Prostate cancer	Phase III	NCT02064673
			Major depression	Phase IV	NCT01750359
Resveratrol	(E)-Stilbene derivate	Electrophilic modification of KEAP1-Cys-151	Type 2 diabetes	Phase I	NCT01677611
			Colon cancer	Phase I	NCT00256334
			COPD	N/A	NCT02245932
			Friedreich ataxia	Phase I/II	NCT01339884
			Nonalcoholic fatty liver	Phase II/III	NCT02030977
			Nonischemic cardiomyopathy	Phase III	NCT01914081
			Endometriosis	Phase IV	NCT02475564
			Chronic renal insufficiency	Phase III	NCT02433925
			Metabolic syndrome X	Phase II	NCT02114892
			Chronic subclinical inflammation; Redox status	Phase III	NCT01492114
			Alzheimer’s disease	Phase II	NCT01504854
				Phase III	NCT00743743
			Huntington disease	Phase III	NCT02336633
CXA-10	Nitro-fatty acid (NFA)	Electrophilic modification of KEAP1-Cys-273 and Cys-288	Acute kidney injury	Phase I	NCT02248051
			Pulmonary arterial hypertension (PAH)	Phase II	NCT03449524
			Primary focal segmental glomerulosclerosis (FSGS)	Phase II	NCT03422510