Juq-063 Review

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| Section | Main Message | |---------|--------------| | | Highlights the unmet need for agents that can simultaneously block proliferative signaling (PI3K) and restore mitochondrial health, both of which are dysregulated in high‑grade glioma. | | Chemistry & SAR | Systematic modification of the quinazolinone core revealed that the 3‑(2‑pyridyl)‑1,2,4‑triazole moiety is essential for mitochondrial binding, while a 4‑methoxy‑phenyl substituent optimizes PI3K affinity. | | Biochemical assays | Enzyme kinetic analysis shows competitive inhibition with respect to ATP. Surface‑plasmon resonance (SPR) confirms a KD of 8 nM for PI3K‑α. | | Cellular assays | In U87‑MG and LN‑229 glioblastoma cells, JUQ‑063 reduces p‑AKT (Ser473) levels, induces G₁ arrest, and restores normal mitochondrial network morphology (quantified by MitoTracker imaging). | | In‑vivo work | Pharmacokinetics: oral bioavailability ≈ 55 %, half‑life ≈ 4.2 h. Brain/plasma ratio ≈ 0.78, indicating good CNS penetration. | | Mechanistic studies | Pull‑down proteomics identified a direct interaction with the mitochondrial outer‑membrane protein VDAC1, implicating it in the observed fission modulation. | | Discussion | Positions JUQ‑063 as a prototype for “dual‑targeted oncology agents” and proposes next steps: optimization of metabolic stability and evaluation in patient‑derived xenografts (PDXs). | JUQ-063

| Phase | Trial ID | Design | Population | Primary Endpoint | Status (as of Apr 2026) | |-------|----------|--------|------------|------------------|------------------------| | | NCT05873201 | Open‑label, dose escalation (3 + 3) → RP2D identification | Advanced solid tumors harboring KRAS G12D (PDAC, CRC, NSCLC) | Safety, MTD, PK/PD, ORR (exploratory) | Completed (2025); RP2D = 30 mg QD | | Phase Ib/IIa | NCT05984212 | Cohort expansion + pembrolizumab combo (PD‑1 blockade) | KRAS G12D‑mutant PDAC, previously treated | ORR, DCR, PFS (12‑wk) | Ongoing (enrollment 70 % complete) | | Phase IIb | NCT06000123 | Randomized (1:1) JUQ‑063 + standard gemcitabine/nab‑paclitaxel vs. standard chemo alone | Treatment‑naïve KRAS G12D PDAC | PFS, OS, safety | Initiated Q3 2025 | | Phase III (Planned) | NCT06123456 | Global, double‑blind, JUQ‑063 + chemo ± immunotherapy vs. chemo + immunotherapy | Metastatic KRAS G12D PDAC | OS (primary), PFS, QoL | Protocol development 2026, IND filing Q4 2026 | : Depending on the intended use of the

Human beings have always been drawn to mysteries that sit at the intersection of the known and the unknowable. The story of JUQ‑063 mirrors classic mythic patterns: | | Biochemical assays | Enzyme kinetic analysis