Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 13, Pages 6241-6261Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00525
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Funding
- Swiss Commission for Technology and Innovation (CTI) by PFLS-LS [14032.1, 15811.2, 17241.1]
- Stiftung fur Krebsbekampfung grant [341]
- Swiss National Science Foundation [310030_153211, 316030_133860, 310030B_138659]
- European Union [675392]
- Cancer Research Society [CRS-22641]
- Marie Curie Actions (MSCA) [675392] Funding Source: Marie Curie Actions (MSCA)
- Swiss National Science Foundation (SNF) [316030_133860, 310030_153211] Funding Source: Swiss National Science Foundation (SNF)
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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.
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