Juy-108

| Chemical Moiety | Contribution | Optimization Path | |---|---|---| | | Provides ATP‑competitive binding to the hinge region of VEGFR‑2/TIE2 | S‑configuration critical for potency (IC₅₀ ≈ 1 nM vs. VEGFR‑2) | | (3‑F‑4‑Me‑phenyl)‑methyl substituent | Enhances hydrophobic contacts within the solvent‑exposed region, boosts oral bioavailability | Fluorine improves metabolic stability; methyl reduces oxidative de‑halogenation | | 2‑pyridin‑3‑yl‑pyrimidine | Drives selectivity for TIE2 by occupying a unique back‑pocket not present in VEGFR‑2 | Substituted pyridine improves solubility, mitigates off‑target kinase binding (e.g., PDGFR‑β) |

| Cohort | Population | Dosing (mg) | Primary Endpoints | Key Secondary Endpoints | |---|---|---|---|---| | (dose‑escalation) | Advanced solid tumours, refractory | 5‑150 mg QD (3 + 3 design) | MTD , DLTs, PK, PD (plasma Ang‑2/VEGF) | ORR, disease control rate (DCR) | | 1B (expansion) | HCC (Child‑Pugh A/B) | RP2D (30 mg QD) | Safety, PK, PD | ORR (RECIST 1.1), PFS, OS | | 1C (expansion) | RCC (clear‑cell, prior VEGF‑TKI) | RP2D (30 mg QD) | Same as 1B | Same as 1B | | 1D (combo) | Advanced solid tumours + anti‑PD‑1 | RP2D + pembrolizumab 200 mg q3w | Safety of combo | ORR, DOR, immune‑related AEs | juy-108

| Parameter | Value | Assay | |---|---|---| | | 0.9 nM | Kinase enzymatic (Eurofins) | | TIE2 IC₅₀ | 0.7 nM | Kinase enzymatic | | Selectivity panel (400 kinases) | > 100‑fold selectivity vs. all other kinases (max off‑target IC₅₀ = > 150 nM) | DiscoveRx KinomeScan | | Cellular phospho‑VEGFR‑2 (HUVEC) | 85 % inhibition at 10 nM | ELISA | | Cellular phospho‑TIE2 (HMEC‑1) | 80 % inhibition at 10 nM | Western blot | | CNS penetration (MDCK‑MDR1 assay) | Efflux ratio = 1.2 (low P‑gp substrate) | In‑vitro transport | | hERG (IC₅₀) | > 30 µM | Patch‑clamp (IonWorks) | | Chemical Moiety | Contribution | Optimization Path