(S)‑4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase

The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is frequently overactivated in cancer, and drives cell growth, proliferation, survival, and metastasis. Here, we report a structure–activity relationship study, which led to the discovery of a drug-like adenosine 5′-triphosphate-site PI3K/mTOR kinase inhibitor: (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)­pyridin-2-amine (PQR530, compound 6), which qualifies as a clinical candidate due to its potency and specificity for PI3K and mTOR kinases, and its pharmacokinetic properties, including brain penetration. Compound 6 showed excellent selectivity over a wide panel of kinases and an excellent selectivity against unrelated receptor enzymes and ion channels. Moreover, compound 6 prevented cell growth in a cancer cell line panel. The preclinical in vivo characterization of compound 6 in an OVCAR-3 xenograft model demonstrated good oral bioavailability, excellent brain penetration, and efficacy. Initial toxicity studies in rats and dogs qualify 6 for further development as a therapeutic agent in oncology.

磷脂酰肌醇3-激酶（phosphoinositide 3-kinase, PI3K）/雷帕霉素靶蛋白（mechanistic target of rapamycin, mTOR）信号通路在癌症中常发生过度激活，可驱动细胞生长、增殖、存活及转移。本研究开展了一项构效关系研究，最终发现一款类药性质的三磷酸腺苷（adenosine 5′-triphosphate, ATP）结合位点型PI3K/mTOR激酶抑制剂：(S)-4-(二氟甲基)-5-(4-(3-甲基吗啉基)-6-吗啉基-1,3,5-三嗪-2-基)吡啶-2-胺（PQR530，化合物6）。该化合物因对PI3K与mTOR激酶的强效性、特异性，以及包括血脑屏障穿透性在内的药代动力学特性，可作为临床候选药物。化合物6对广泛的激酶谱展现出优异的选择性，同时对非相关受体酶与离子通道亦表现出良好的选择性。此外，化合物6可抑制多种癌细胞系的细胞生长。在OVCAR-3异种移植模型中对化合物6开展的临床前体内表征研究显示，其具备良好的口服生物利用度、优异的血脑屏障穿透性及抗肿瘤功效。针对大鼠与犬开展的初步毒性研究表明，化合物6具备进一步开发为肿瘤治疗药物的潜力。