Some people have compromised NRF2 function, which you can find out if you use biomni to alphagenome ur entire genome and then run a graphKB pathway analysis via michelle li’s PINNACLE/ayush noori’s intervention graph.
This is exactly the bidirectional perturbagen evidence I need, and it’s real Open Targets data. Key findings:
Directional pharmacology available (real drugs/candidates):
- HSP90AA1/AB1: 10 drugs each, all INHIBITORs (retaspimycin, luminespib, onalespib, BIIB021…) — HSP90 inhibition is well-developed but note it’s a stress-inducer paradoxically (HSP90 inhibition releases HSF1 → induces HSR). Bidirectionally relevant.
- KEAP1: INHIBITOR/ANTAGONIST — dimethyl fumarate (APPROVED, an MS drug), diroximel/monomethyl fumarate. KEAP1 inhibition = NRF2 activation (boosts the glutathione arm) — a clean actionable lever.
- NFE2L2/NRF2: ACTIVATOR — omaveloxolone (APPROVED for Friedreich’s ataxia!), bardoxolone (Phase 3). Direct NRF2 activation to boost antioxidant defense.
- MAP3K5/ASK1: INHIBITOR — selonsertib (Phase 3). The redox-stress bridge kinase.
- SOD1: ANTISENSE INHIBITOR — tofersen (APPROVED for SOD1-ALS).
- HSPB1: antisense inhibitor (apatorsen); HSPA8/HSPA1A: inhibitors; TXN: PX-12 inhibitor.
Tractable but no drug yet: HSF1 (high-quality ligand — activatable), GCLC (druggable family), EIF2AK3/PERK (druggable), STUB1 (structure-based only), PARK7, PRDX1, SLC7A11 (all have small-molecule binders).
The directionality here is crucial for the bidirectional framing. Now let me build the consolidated bidirectional perturbagen nomination table, combining leverage rank + direction + what pharmacology exists + the biologically-motivated “boost” agents (NAC, GGC, sulforaphane for the glutathione arm; HSF1 co-inducers). Let me assemble this.