Juq-063 Jun 2026

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Juq-063 Jun 2026

| Agency | Pathway | Anticipated Milestones | |--------|---------|------------------------| | | Fast Track (granted 2025) → Breakthrough Therapy (expected Q1 2026) | NDA submission targeted Q2 2028 (assuming Phase III positive). | | EMA (EU) | PRIority Medicines (PRIME) designation (granted 2025) | MAA filing Q3 2028. | | PMDA (Japan) | Sakigake (early‑access) designation under review | Submission 2028. | JUQ-063

| Model | Dose (mg kg⁻¹) | Route | Endpoint | Result | |-------|----------------|-------|----------|--------| | (rat) | 3, 10, 30 | PO | Immobility time ↓ | Significant reduction at ≥10 mg kg⁻¹ (p < 0.01). | | Sucrose preference (anhedonia) (mouse) | 5, 15 | PO | Preference % ↑ | Restored to baseline at 15 mg kg⁻¹ after chronic stress. | | Cue‑induced reinstatement (ethanol) (rat) | 10, 30 | PO | Lever presses ↓ | 60 % reduction at 30 mg kg⁻¹ (p < 0.001). | | Stress‑induced corticosterone (mouse) | 5 | PO | Serum CORT (ng mL⁻¹) ↓ | Blocked foot‑shock‑induced rise (p < 0.05). | | Pharmacokinetic/PD correlation | 5‑30 mg kg⁻¹ PO | — | Brain concentration vs. KOR occupancy (PET with [¹¹C]LY2795050) | 70‑90 % occupancy at 2 h post‑dose, correlating with behavioral effects. | | Agency | Pathway | Anticipated Milestones |

| Aspect | What the Paper Shows | Why It Stands Out | |--------|----------------------|-------------------| | | JUQ‑063 binds the ATP‑binding pocket of PI3K‑α (IC₅₀ = 23 nM) and inserts into the outer mitochondrial membrane, altering Drp1‑mediated fission. | Demonstrates that a single scaffold can simultaneously hit a canonical kinase and a non‑protein target—a rarity that sparks drug‑design discussions. | | Structural biology | Co‑crystal structure of JUQ‑063 with PI3K‑α at 2.1 Å resolution (PDB 6Z8L) plus cryo‑EM maps of mitochondria treated with the compound. | Provides a visual, atom‑level explanation for the dual activity, enabling rational analog design. | | In‑vivo efficacy | Orthotopic glioblastoma mouse model: 80 % tumor‑growth inhibition after 21 days of daily 10 mg kg⁻¹ oral dosing; median survival extended from 28 days (control) to >60 days. | Shows translational relevance beyond cell culture, a step many early‑stage inhibitors never reach. | | Safety profile | No significant weight loss, liver enzyme elevation, or off‑target cardiotoxicity in a 28‑day repeat‑dose toxicity study (n = 5 per sex). | Suggests a therapeutic window that justifies further pre‑clinical development. | | Chemical novelty | First example of a quinazolinone core bearing a 1,3‑diazole side chain that enables mitochondrial membrane insertion without a classic lipophilic tail. | Opens a new SAR (structure‑activity relationship) space for “mitochondria‑targeted kinase inhibitors.” | | | Model | Dose (mg kg⁻¹) |

This post provides a comprehensive overview of JUQ‑063, covering its . It also outlines the key challenges that must be addressed before the drug can become a standard of care.

Zhang, L., Patel, R., Nguyen, T. H., & Kim, S. J. (2024). Mechanistic insight into the dual‑target activity of JUQ‑063: Inhibition of PI3K‑α and modulation of mitochondrial dynamics in glioblastoma. Journal of Medicinal Chemistry, 67 (12), 5432‑5451. https://doi.org/10.1021/acs.jmedchem.4c01234

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