Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood–brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound’s safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.

中文翻译：

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5-（4,6-Dimorpholino-1,3,5-triazin-2-yl）-4-（trifluoromethyl）pyridin-2-amine（PQR309），有效，可渗透脑，口服生物有效性，泛I类PI3K / mTOR抑制剂作为肿瘤学的临床候选药物

磷酸肌醇3-激酶（PI3K）在多种人类肿瘤中均失活，并触发蛋白激酶B（PKB / Akt）和哺乳动物雷帕霉素靶标（mTOR）的激活。在这里我们描述了化合物1（PQR309，bimiralisib）的临床前表征，这是一种有效的4,6-dimorpholino-1,3,5-三嗪类泛I类PI3K抑制剂，它以较高的浓度以平衡的方式靶向mTOR激酶。在广泛的蛋白激酶，酶和受体配体分析中，没有检测到1的脱靶相互作用。此外，1个不结合微管蛋白，这在结构上相关的4个中被观察到（BKM120，buparlisib）。化合物1可口服，可穿过血脑屏障，并在小鼠，大鼠和狗中显示出良好的药代动力学参数。化合物1显示出在肿瘤细胞系和大鼠异种移植模型中抑制增殖的效率。这与该化合物的安全性一起，将1鉴定为在肿瘤学（包括脑肿瘤或CNS转移瘤）的广泛应用范围内的临床候选药物。化合物1目前正在进行晚期实体瘤和难治性淋巴瘤的II期临床试验。