Juq-139

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 (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 (K i = 0.42 nM), selective inhibition over the PI3K‑β/δ/γ isoforms (>500‑fold), and potent antiproliferative activity (IC 50 = 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.

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). JUQ-139