The opportunity

Session 3 at the 2026 SMA Congress (Budapest) put metabolism and redox back on the map. Vrettou et al. (Cologne, O16, bioRxiv 2026-01-09) show SMN deficiency collapses the NRF2–KEAP1 antioxidant response in SMA liver, drives ferroptotic vulnerability, and — critically — SMN-restoring ASO therapy only partially rescues this axis. Persistent heme pathway activation and NRF2 repression leave a window open for NRF2 activators as a combination therapy alongside nusinersen / risdiplam / onasemnogene.

This axis is clinically validated in adjacent inherited neurodegeneration:

• Omaveloxolone (Skyclarys) — FDA-approved 2023 for Friedreich ataxia. Covalent KEAP1 Cys151 activator. Closest analog for SMA repurposing.
• Dimethyl fumarate (Tecfidera) — approved for multiple sclerosis. Active metabolite MMF covalently modifies KEAP1 Cys151.
• Bardoxolone methyl (CDDO-Me) — late-stage clinical development, potent triterpenoid activator.
• Sulforaphane — natural isothiocyanate, cheap tool compound.

Structural targets

• KEAP1 Kelch domain — PDB 7OFE (non-covalent fragment Ki = 280 nM), PDB 4L7B, PDB 4XMB. UniProt Q14145.
• NRF2 (NFE2L2) — Neh2 ETGE/DLG motifs, the PPI interface with KEAP1. UniProt Q16236.

Hotspot residues: Arg415, Arg483, Ser508, Tyr572, Tyr334.

Our campaign

Compound set: omaveloxolone, bardoxolone methyl, sulforaphane, DMF, monomethyl fumarate, oltipraz, curcumin, KI-696 (non-covalent benchmark, Kd = 1.3 nM), ML334 (reversible PPI inhibitor), and ML-385 (NRF2 inhibitor, negative control). DiffDock against the KEAP1 Kelch domain + 100 ns MD + MM-PBSA ranking on top hits. Results expected within 24–48 hours.

Why we are first

No published NRF2-selective compound is in SMA clinical development. We believe we are the first platform to propose this as a combination therapy framework for SMA. See the Simon 3-mechanism combo memo for how this stacks with Fasudil (cytoskeletal) and ARGX-119-like (NMJ).

References: Vrettou et al. 2026 bioRxiv, PMID 39243573 ferroptosis in Friedreich ataxia, PMID 31640150 comparative NRF2 drugs in FA.