期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 17, 页码 7524-7538出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00930
关键词
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资金
- Swiss Commission for Technology and Innovation (CTI) by PFLS-LS Grants [14032.1, 15811.2, 17241.1]
- Stiftung fur Krebsbekampfung Grant [341]
- Swiss National Science Foundation [310030_153211, 316030_133860, 310030B_138659]
- European Union's Horizon research and innovation program under the Marie Sklodowska-Curie Grant [675392]
- MRC [MC_U105184308]
- Swiss National Science Foundation (SNF) [310030_153211, 316030_133860] Funding Source: Swiss National Science Foundation (SNF)
- Medical Research Council [MC_U105184308] Funding Source: researchfish
- MRC [MC_U105184308] Funding Source: UKRI
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.
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