Juq-139 ❲iPad Complete❳

Juq-139 ❲iPad Complete❳

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Please provide more details so I can assist you effectively! JUQ-139

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The phosphoinositide 3‑kinase (PI3K) pathway is a central regulator of cell growth, metabolism, and survival, and its dysregulation is a hallmark of many malignancies (Miller et al., 2020). Among the class I PI3K isoforms, PI3K‑α (p110α) is frequently mutated (e.g., H1047R) or amplified in breast, colorectal, and endometrial cancers (Samuels et al., 2019). While several PI3K‑α inhibitors have entered clinical trials (e.g., alpelisib), dose‑limiting toxicities and off‑target effects underscore the need for more selective, orally bioavailable scaffolds (Liu & Cheng, 2022). Please provide more details so I can assist you effectively

Our group previously identified a 1,3‑benzothiazole‑based series (compound series JX‑1) that displayed modest PI3K‑α inhibition (K_i ≈ 120 nM) but suffered from poor metabolic stability (Patel et al., 2021). In an effort to improve potency, selectivity, and pharmacokinetic (PK) properties, we pursued a hybrid design merging the benzothiazole core with a pyrazolo[1,5‑a]pyridine fragment, a privileged motif known to enhance kinase binding through a hinge‑region hydrogen bond (Wang et al., 2018). The resulting molecule, JUQ‑139, incorporates a sulfonamide tether bearing a para‑fluorophenyl‑propyl side chain to improve oral absorption and metabolic stability.

In this report we describe:

Athymic nude mice (5‑week‑old, n = 8 per group) were subcutaneously implanted with 5 × 10⁶ MDA‑MB‑231 cells in Matrigel. When tumors reached ~150 mm³, mice received either vehicle (0.5 % methylcellulose) or JUQ‑139 (30 mg kg⁻¹, oral, q.d.) for 21 days. Tumor volumes were measured with calipers (V = ½ L × W²) and body weight monitored. At study termination, tumors were excised for immunoblotting of p‑AKT (S473) and Ki‑67.