Current status (Q1 2026):
| 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) | juy-108