h01 — Pharmacochaperone E1659A

mech. Small-molecule fold-stabilizer binds K1141 pocket on E1659A STRC, rescuing misfolded stereocilin. delivery. Oral/topical small molecule; round-window permeability precedent exists. patient-fit. Maternal allele c.4976A>C E1659A directly targeted; extracellular concern flags mechanism.

status

A-tier. Reframed from “NORMAL monotherapy” → “MILD-MODERATE adjunct lever with conditional NORMAL” per Misha Compound-Het Therapy Stack Model. K1141 pocket site-druggable (Phase 5c GREEN), chemistry-limited on current shortlist (Phase 5b RED); fenamic parents not developable for pediatric target per STRC h01 Fenamic Scaffold Tox Audit 2026-04-23, tafamidis-style bioisosteric optimization is the forward path.

active compute

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next-step tree

After v3b delivery:

1. GREEN non-covalent → Phase 4h MD-scored validation on top-5 + wet-lab triage STRC h01 Phase 8 Wet-Lab Triage SOP on tafamidis-style optimized analog (parents are MD probes only per tox audit)
2. GREEN covalent → Phase 6c selectivity audit vs proteome-wide Lys pockets + cochlear ion-channel panel (TRPM4 / Cx50 / BK / KCNQ4 / TMEM16A)
3. YELLOW → Phase 3c v4 fragment-growing on best cluster OR Phase 6d different warhead class
4. RED → Phase 3c v5 de novo RFdiffusion pocket design

After Phase 5d + 5e delivery:

• Mutant K1141 stable (ΔΔG < 0.3 kcal/mol, Kd ratio < 2×) → WT-based docking validated, continue medchem on v3b hits
• Mutant pocket shifts → Phase 3c v6: re-screen on mutant ensemble, or pivot to h11 dimer-interface rescue
• Mutant reveals new cryptic pocket → Phase 3c v7 new-pocket screen

Recent activity

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• h01 log
• strc
• h01
• Phase 3c v3b + 6b: 0 GREEN / 29 YELLOW / 21 RED on 12,253-ligand ensemble dock. Ceiling mean ΔG −7.28 kcal/mol (Kd 4.57 µM, f_PC 0.34) — 6.6× lower Kd than v2 fenamic (30 µM) via 3-amino-benzofuran-2-COOH scaffold. Crosses MILD-MODERATE adjunct threshold (f_PC 0.30), short of NORMAL (0.50). Top YELLOW cluster tight on benzofuran-2-COOH body + naphthyl/biphenyl tails + CONHOH/tetrazole acid bioisostere + −CF₃. A held. → STRC h01 Phase 3c v3b + 5d Delivery 2026-04-24
• Phase 5d E1659A full-length MD: delivered 2 ns / 20 snapshots (not planned 10 ns; 14.06 ns/day Metal-OpenCL, production-10ns-ETA was 17.1 h). First MD on actual disease target (1,775-res AF3 E1659A, 651k-atom solvated); closes WT-Ultra-Mini gap. K1141/E1659 mutations verified. A held. → STRC h01 Phase 3c v3b + 5d Delivery 2026-04-24

evidence

• STRC Pharmacochaperone Virtual Screen E1659A — main hypothesis; Phases 0-3
• STRC Pharmacochaperone K1141 Fragment Pocket — pocket characterization
• STRC Pharmacochaperone Phase 4 Plan — 7-gate validation ladder
• STRC h01 Phase 4h Tafamidis Playbook Library 2026-04-23 — 30-compound bioisostere seed
• STRC h01 Phase 8 Wet-Lab Triage SOP — 3-gate wet-lab protocol
• STRC h01 Fenamic Scaffold Tox Audit 2026-04-23 — scaffold developability
• STRC h01 Phase 5 MD Ensemble Rescoring 2026-04-23 — Phase 5a/5b
• STRC h01 Phase 5c Cryptic Pocket Analysis 2026-04-23 — site stability
• STRC h01 Phase 3c v2 Expanded Screen 2026-04-23 — expanded dock

scripts

See STRC Computational Scripts Inventory § Hypothesis 1.

log

h01 log

cross

• STRC Electrostatic Analysis E1659A — electrostatic input to pocket design
• STRC Mini-STRC Single-Vector Hypothesis — h03 is parallel S-tier, not fallback
• Misha Compound-Het Therapy Stack Model — h01 is Misha’s only monotherapy-to-NORMAL route

Connections

• [part-of] STRC Hypothesis Ranking
• [about] Misha