Table 1 Summary of the drug development status of NRF2 activators
Compound | Mechanism of action | Disease | Development stage | Trial/References |
|---|---|---|---|---|
KEAP1-dependent NRF2 activators | ||||
 Electrophilic compounds | ||||
  Cyanoenone triterpenoids. | ||||
   Bardoxolone methyl (BARD, CDDO-Me, RTA402) | Modification of C151 in KEAP1 | Alport syndrome | Phase II/III (active) | CARDINAL/NCT03019185 |
Autosomal dominant polycystic kidney disease | Phase II (completed) | PHOENIX/NCT03366337 | ||
PAH | Phase III (active) | RANGER/NCT03068130 | ||
   Omaveloxolone | Modification of C151 in KEAP1 | Diabetic chronic non-healing wounds | Preclinical | [277] |
FRDA | Phase II (active) | MOXIe/NCT02255435 | ||
  Fumaric acid esters. | ||||
   Dimethylfumarate (DMF) | Modification of C151 in KEAP1 | Psoriasis | Approved | [281] |
MS | Approved | PROTEC/NCT01930708 | ||
   VCB102 | Modification of C151 in KEAP1 | Psoriasis | Preclinical | V ClinBio LLC |
   VCB101 | Modification of C151 in KEAP1 | MS | Preclinical | V ClinBio LLC |
   CAT4001 | Modification of C151 in KEAP1 | FRDA | Preclinical | Catabasis Pharmaceuticals |
   XP23829 | Modification of C151 in KEAP1 | Psoriasis | Phase II (completed) | |
   ALK8700/BIIB098 | Modification of C151 in KEAP1 | MS | Phase III (completed) | EVOLVE-MS-2/NCT03093324 |
  Hydroxylamine. | ||||
   N-tert-butyl hydroxylamine | Targeting of KEAP1 | Retinal pigment epithelial cells | in vitro | [285] |
   OT551 | Targeting of KEAP1 | Age-related macular degeneration | Phase II (completed) | OMEGA/NCT00485394 |
  Nitro fatty acids. | ||||
   CXA10 | Modification of C273 and C288 in KEAP1 | PAH | Phase II (completed) | PRIMEx/NCT03449524 |
Primary focal segmental glomerulosclerosis | Phase II (completed) | FIRSTx/NCT03422510 | ||
   NATOH, NATxME and NATx0 | Modification of C273 and C288 in KEAP1 | Inflammation related diseases | in vitro/Preclinical | [288] |
  Sulforaphane. | ||||
   Sulforaphane (SFN) | Modification of C151 in KEAP1 | Autism spectrum disorder | Phase II (active) | |
Hypoxic-ischemic injury, AD, PD | Preclinical | [292] | ||
   Melatonin–sulforaphane hybrid (ITH12674) | Modification of C151 in KEAP1 | Neuronal OS | in vitro | [293] |
   SFX-01 | Modification of C151 in KEAP1 | ER+ metastatic breast cancer | Phase II (completed) | STEM/NCT02970682 |
Subarachnoid hemorrhage | Phase II (completed) | SAS/NCT02614742 | ||
  TFM735. | ||||
   TFM735 | Modification of C151 in KEAP1 | EAE models of MS | Preclinical | [297] |
 Non-electrophilic compounds | ||||
   Naphthalene bis-sulfonamides, Tetrahydroisoquinolines, and Molecules with an oxa-diazole motif | KEAP1-NRF2 PPI inhibition | COPD | in vitro/Preclinical | [298] |
   DEETGE-CAL-Tat synthetic peptide | KEAP1-NRF2 PPI inhibition | Brain injury | Preclinical | [301] |
GCI | Preclinical | [302] | ||
KEAP1-independent NRF2 activators | ||||
  BACH1 inhibitors. | ||||
   HPP-4382 | BACH1 inhibition | Lung fibroblasts | in vitro | [303] |
   HPP971 | BACH1 inhibition | EAE models of MS | Phase I (completed) | [304] |
Blood, Bone, Eye, Kidney, and Lung diseases | Phase II (completed) | vTv Therapeutics | ||
  HRD1 inhibitors. | ||||
   LS-102 | HRD1 inhibition | Liver cirrhosis | in vitro/Preclinical | [228] |
  GSK-3β inhibitors. | ||||
   Nordihydroguaiaretic acid | GSK3-β inhibition | Prostate cancer | Phase II (completed) | |
Brain and CNS tumors | Phase I/II (completed) | |||
   Terameprocol | GSK3-β inhibition | High grade glioma | Phase I (active) | |
   Enzastaurin | GSK3-β inhibition | Diffuse large B-Cell lymphoma | Phase III (active) | |
  p62 activators. | ||||
   Trehalose | p62 activation | Hepatoma cells | in vitro | [308] |
   Rapamycin | p62 activation | FRDA | Preclinical | [309] |
Systemic lupus erythematosus | Phase II (completed) | |||
Diabetes mellitus type1 | Phase III (completed) | |||
Autosomal dominant polycystic kidney disease | Phase II (stopped) | |||
ALS | Phase II (active) | RAP-ALS/NCT03359538 | ||