STRC Research

log

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h09 log

2026-04-23

  • Phase 4i Kd × Kd sensitivity sweep (5×5, KD_TMEM145 10 nM-10 μM × KD_WH2_FACTIN 1 μM-1 mM) on therapeutic window: f≥0.3 reachable on 80% of plausible grid (PASS 56% single-dose + MARGINAL 24%); FAIL 20% concentrated at WH2 Kd = 1 mM column (Tβ4 analog floor, toxic ceiling beats f=0.3). Strategic finding: WH2 Kd dominates, TMEM145 Kd is secondary. Reorders wet-lab priority → Phase 2c WH2 bundling gate #1; TMEM145 SPR/BLI → #2 (ipSAE already operable-band-placed). Verdict A_hold_multi_dose_ok, not S-robust (70% PASS threshold). A held, Mech 4 held, Deliv 3 held. → STRC h09 Phase 4i Kd Sensitivity Sweep 2026-04-23
  • Dunbrack 2025 ipSAE reassessment on Ultra-Mini × TMEM145 CIFs: GOLD pruned ipSAE 0.591 sits in known-binder-zone (NFAT-CnB 0.55 … NFAT-CnA 0.78 physiological binders) → gate 3 (STRC×TMEM145 Kd) narrowed: placeholder 100 nM now lit-band-consistent (10 nM-10 µM Calcineurin-family band) instead of “arbitrary”; absolute Kd still wet-lab-gated. Full-length ipSAE 0.014 reaffirms known TM-collapse AF3 limit. Path B (AF3-only absolute Kd calibration) closed as lit-infeasible. A held, Mech 4 held. → STRC ipSAE Cross-Complex Reassessment 2026-04-23
  • Phase 4e_v2 blend scaffold model: closes 1/3 S-tier gate (118 aa tail > 12 aa empirical RADA16 limit). Recommended design point φ_tail=0.05 (5% RADA16-tail91, 95% plain), 2% w/v gel: PASS flag (within Gelain hybrid lit range), 6.4×10⁷ tails per OHC bundle shell, 2000× valency excess vs putative 3×10⁴ TMEM145 sites/bundle low est, 3.8× dose cost vs hypothetical 100% tail91. Gates 2 (WH2×F-actin Kd) + 3 (STRC×TMEM145 Kd) still open (wet-lab or Path B AF3 calibration). A held, Mech 4 held, Deliv 3 held. → STRC h09 Phase 4e_v2 Blend Scaffold
  • Hub-note status banner added: both load-bearing unmeasured Kds (STRC×TMEM145 100 nM placeholder; WH2×F-actin 5 μM optimistic vs Tβ4 5-10 mM analog) + tail-91 > 12 aa RADA16 modification limit logged as promotion-to-S gates. Unsourced “48 h actin t½” in note replaced with Zhang 2012 Nature primary data (shaft stable months; tip β-actin t½ hours). A held. → STRC Synthetic Peptide Hydrogel HTC
  • Parameter provenance audit: 3 critical gaps (118 aa tail, WH2×F-actin Kd, STRC×TMEM145 Kd); 7 phantom/wrong values; Mech 5→4 Deliv 4→3 (A held); triple promotion gate to S → STRC h09 Parameter Provenance Audit 2026-04-23
  • Phase 4d/4e/4h re-run with lit-backed parameters: PERILYMPH_VOL 70→34 μL (Dhanasingh 2021); K_RWM 0.02→0.003 /h (Salt & Ma 2001, prior PHANTOM); K_CLEAR_ME 0.35→0.7 (Salt & Plontke 2018); K_PERILYMPH 0.35→0.18 (Salt & Hartsock 2015); K_PROTEOLYSIS 1.4→0.05 (⚠ still unmeasured); STEREOCILIA_SPACING 12→9 nm (Krey 2016 plastin, was espin-specific). Therapeutic window (1-10 μM, 2 log units) survives swap. WH2×F-actin Kd + STRC×TMEM145 Kd remain load-bearing placeholders. A held. → STRC h09 Parameter Provenance Audit 2026-04-23
  • Phase 3b full-construct: tail91 PASSES TMEM145 0.57 + actin 0.51; tail71 FAILS TMEM145 catastrophically (0.35) → STRC Hydrogel HTC Phase 1 Self-Assembly
  • B → A: mechanism 3→5; Phase 3 tail retool ipTM 0.68 = Ultra-Mini GOLD baseline → STRC Hydrogel HTC Phase 1 Self-Assembly
  • Phase 4 8-axis campaign: Delivery 3→4; PKPD window 0.13-1.32 mg; $42/ear GMP; MODERATE immunogenicity → STRC Hydrogel Phase 4 Computational Campaign
  • Phase 4b AF3 batch built (8 jobs); awaiting submission → STRC Hydrogel Phase 4 Computational Campaign
  • Phase 3 tail retool: design bug found (wrong epitope Phase 1); 91 aa correct-epitope tail ipTM 0.68 → STRC Hydrogel HTC Phase 1 Self-Assembly
  • Phase 3 retool batch built (3 jobs): 51/71/91 aa tails; gate ipTM ≥ 0.50 → STRC Hydrogel HTC Phase 1 Self-Assembly
  • Phase 2 AF3: actin PASS (0.59), TMEM145 FAIL (0.37-0.39, wrong-epitope tail confirmed) → STRC Hydrogel HTC Phase 1 Self-Assembly
  • Phase 2 AF3 batch built (6 jobs: 3 candidates × TMEM145 + actin trimer) → STRC Hydrogel HTC Phase 1 Self-Assembly
  • Phase 1 analytical: 5/6 pass all gates; top-3 shortlisted → STRC Hydrogel HTC Phase 1 Self-Assembly

2026-04-23

  • #9 Hydrogel: A held, Mech 4 held, Deliv 3 held. Phase 4i Kd × Kd 5×5 sensitivity sweep on therapeutic window: f ≥ 0.3 reachable on 80% of plausible grid (PASS 56% single-dose ≤ 5 mg + MARGINAL 24% at 5-20 mg); FAIL 20% only at WH2 Kd ≥ 1 mM (Tβ4 analog floor) where G-actin toxicity ceiling hits before f=0.3 achievable. Strategic reorder: WH2×F-actin Kd dominates, TMEM145 Kd secondary. Phase 2c WH2 bundling (HEK293 GFP-actin confocal) now wet-lab gate #1; TMEM145 SPR/BLI → #2 (ipSAE already places in operable band). Verdict A_hold_multi_dose_ok — S promotion still requires WH2 Kd narrowing. → STRC h09 Phase 4i Kd Sensitivity Sweep 2026-04-23
  • #9 Hydrogel + #26 Homodimer: ipSAE (Dunbrack 2025) reassessment on 6 STRC AF3 jobs (incl. 2 known positive + 2 known negative controls). Ultra-Mini × TMEM145 GOLD ipSAE 0.591 sits in known-binder-zone (NFAT-CnB 0.55 … NFAT-CnA 0.78 physiological binders) → h09 gate 3 narrowed from “unsupported placeholder” to “band-consistent 10 nM-10 µM, wet-lab still gating absolute Kd”; A held, Mech 4 held. Ultra-Mini homodimer ipSAE 0.000 (zero interface residues pass PAE<10 Å) contradicts prior ipTM 0.28-0.30 weak-binder interpretation per Dunbrack’s disordered-region-false-positive fix → #26 Mech 3→2, B held. Path B (AF3 absolute Kd calibration) closed as lit-infeasible. → STRC ipSAE Cross-Complex Reassessment 2026-04-23
  • #9 Hydrogel: A held. Phase 4e_v2 blend scaffold model closes 1/3 S-tier gate (118 aa tail > 12 aa empirical RADA16 modification limit). φ_tail=0.05 (5% blend) PASS flag per Frontiers 2021 extrapolation; 2000× valency excess vs putative TMEM145 sites per OHC bundle; 3.8× dose cost vs hypothetical 100% tail91. Gates 2 (WH2×F-actin Kd) + 3 (STRC×TMEM145 Kd) still open. → STRC h09 Phase 4e_v2 Blend Scaffold
  • #9 Hydrogel hub note: A held. Status banner added documenting both load-bearing unmeasured Kds (STRC×TMEM145, WH2×F-actin side-binding) and tail-91 > 12 aa RADA16 limit as promotion-to-S gates. Unsourced “actin t½ 48 h” in note replaced with Zhang 2012 Nature primary data (stereocilia shaft stable over months; tip β-actin t½ hours). → STRC Synthetic Peptide Hydrogel HTC
  • #9 Hydrogel: B → A. Mechanism 3→5. Phase 3 tail91 ipTM 0.68 matches Ultra-Mini GOLD baseline. → STRC Hydrogel HTC Phase 1 Self-Assembly
  • #9 Hydrogel: A confirmed at full-construct scale. tail91 passes TMEM145 0.57 + actin 0.51. → STRC Hydrogel HTC Phase 1 Self-Assembly
  • #9 Hydrogel: Delivery 3→4. Phase 4 8-axis campaign: clean PKPD window 0.13-1.32 mg. → STRC Hydrogel Phase 4 Computational Campaign
  • #9 Hydrogel Parameter Audit: Mech 5→4, Deliv 4→3 (A held). 3 critical lit gaps (118 aa tail > 12 aa limit; WH2×F-actin Kd no primary; STRC×TMEM145 Kd no primary); 7 phantom/wrong constants. Promotion gate to S now triple: 4b + blend model + Phase 2c. → STRC h09 Parameter Provenance Audit 2026-04-23
  • #9 Hydrogel Phase 4d/4e/4h re-run: A held. Lit-backed parameters swapped in-place: PERILYMPH_VOL 70→34 μL (Dhanasingh 2021); K_RWM 0.02→0.003 /h (Stokes-Einstein from Salt & Ma 2001, prior cite PHANTOM); K_CLEAR_ME 0.35→0.7 (Salt & Plontke 2018); K_PERILYMPH 0.35→0.18 (Salt & Hartsock 2015); K_PROTEOLYSIS 1.4→0.05 (t½ 14 h, still ⚠); STEREOCILIA_SPACING 12→9 nm (Krey 2016 plastin). Therapeutic window (1-10 μM, 2 log units) survives swap. WH2×F-actin Kd load-bearing unmeasured; STRC×TMEM145 Kd placeholder. → STRC h09 Parameter Provenance Audit 2026-04-23

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