JUQ‑139 is a newly designed heterocyclic small‑molecule that combines a 1,3‑benzothiazole core with a fused pyrazolo[1,5‑a]pyridine moiety, functionalized with a sulfonamide‑linked aryl‑alkyl side chain. The compound was conceived through a structure‑based drug‑design (SBDD) campaign targeting the ATP‑binding pocket of the oncogenic kinase PI3K‑α (phosphoinositide 3‑kinase alpha). Here we report a convergent synthetic route to JUJ‑139, its physicochemical profiling, in‑vitro kinase inhibition, cytotoxicity against a panel of cancer cell lines, and preliminary in‑vivo efficacy in a xenograft mouse model. JUQ‑139 exhibits sub‑nanomolar affinity for PI3K‑α (Ki = 0.42 nM), selective inhibition over the PI3K‑β/δ/γ isoforms (>500‑fold), and potent antiproliferative activity (IC50 = 12–38 nM) in triple‑negative breast cancer (TNBC) and KRAS‑mutant colorectal cancer (CRC) cell lines. Oral administration (30 mg kg⁻¹ q.d.) in athymic nude mice bearing MDA‑MB‑231 xenografts produced a 78 % tumor growth inhibition (TGI) with no observable toxicity. These data position JUQ‑139 as a promising lead for further preclinical development toward targeted cancer therapy.
Keywords: JUQ‑139, PI3K‑α inhibitor, heterocyclic scaffold, anticancer, structure‑based drug design, kinase selectivity JUQ-139
All reagents were purchased from Sigma‑Aldrich, TCI, or Alfa Aesar and used without further purification unless noted. Reaction progress was monitored by thin‑layer chromatography (TLC) on silica gel 60 F254 plates and visualized under UV (254 nm). Purifications were performed by flash chromatography (SiO₂, 30–70 % EtOAc/hexanes) or preparative HPLC (C₁₈, 5–95 % acetonitrile in water, 0.1 % formic acid). NMR spectra were recorded on a Bruker Avance III 600 MHz spectrometer; HR‑MS data were obtained on an Agilent Q‑TOF LC‑MS system. All reagents were purchased from Sigma‑Aldrich, TCI, or
Male CD‑1 mice (n = 3 per time point) received a single oral dose of JUQ‑139 (30 mg kg⁻¹) formulated in 0.5 % methylcellulose. Plasma samples were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 h, processed by protein precipitation, and analyzed by LC‑MS/MS (LLOQ = 5 ng mL⁻¹). Non‑compartmental analysis (Phoenix WinNonlin) yielded the following PK parameters: Cmax = 2.4 µg mL⁻¹, Tmax = 1 h, AUC₀–∞ = 15 µg·h mL⁻¹, t½ = 6.8 h, oral bioavailability ≈ 45 %. All reagents were purchased from Sigma‑Aldrich
| Parameter | Method | Result | |-------------------------|-------------------------------------|--------| | Aqueous solubility (pH 7.4) | Kinetic shake‑flask (25 °C) | 12 µM | | Log D7.4 (octanol/water) | HPLC‑based pH‑stat | 2.1 | | PAMPA permeability | Parallel artificial membrane assay | 1.8 × 10⁻⁶ cm s⁻¹ | | Microsomal stability (human) | 30 min incubation with pooled HLM, NADPH | t½ = 85 min | | CYP inhibition (IC₅₀) | Panel of CYP3A4, 2C9, 2D6 | >10 µM (no inhibition) |