Juq-565 -

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Database registry IDs for chemical compounds, genetic sequences, or astronomical objects. JUQ-565

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JUQ‑565 is a recently discovered heterocyclic scaffold (C₁₈H₁₆N₄O₂) identified through a high‑throughput phenotypic screen targeting the phosphoinositide‑3‑kinase (PI3K)–Akt signaling axis in aggressive breast cancer models. Here we present a comprehensive pre‑clinical evaluation of JU‑565, covering synthetic route optimization, in‑vitro pharmacology, structure‑activity relationship (SAR) expansion, and in‑vivo efficacy in orthotopic xenograft models of triple‑negative breast cancer (TNBC). JUQ‑565 demonstrates sub‑nanomolar inhibition of PI3Kα (IC₅₀ = 0.42 nM) with >10,000‑fold selectivity over PI3Kβ/γ/δ, robust downstream Akt de‑phosphorylation, and potent antiproliferative activity (GI₅₀ = 8 nM) across a panel of TNBC cell lines. Pharmacokinetic profiling reveals high oral bioavailability (F = 62 %) and favorable tissue distribution, achieving therapeutic concentrations (> 10× IC₅₀) in tumor tissue for > 12 h after a single dose. In orthotopic mouse models, once‑daily oral dosing (30 mg kg⁻¹) resulted in a 78 % tumor growth inhibition (TGI) without overt toxicity. Mechanistic studies indicate that JUQ‑565 also sensitizes TNBC cells to DNA‑damage–inducing agents (e.g., carboplatin) through inhibition of Akt‑mediated DNA repair pathways. Together, these data position JUQ‑565 as a promising clinical candidate for PI3K‑driven malignancies, especially TNBC, and provide a blueprint for its further development.

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