The phosphoinositide 3-kinase (PI3K) / mechanistic target of rapamycin (mTOR) pathway is frequently overactivated in cancer, and drives cell growth, proliferation, survival, and metastasis. The paper reports a structure–activity relationship study, which led to the discovery of a PI3K/mTOR kinase inhibitor (PQR530), which qualifies as a clinical candidate due to its potency and specificity for PI3K and mTOR kinases, and its pharmacokinetic properties, including brain penetration. PQR530 showed excellent selectivity over a wide panel of kinases and an excellent selectivity against unrelated receptor enzymes and ion channels. Moreover, it prevented cell growth in a cancer cell line panel. The preclinical in vivo characterization of PQR530 in an OVCAR-3 xenograft model demonstrated good oral bioavailability, excellent brain penetration, and efficacy. Initial toxicity studies in rats and dogs qualify PQR530 for further development as a therapeutic agent in oncology.