5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

被引：122

作者：

Beaufils, Florent ^{[1
,3
,5
]}

Cmiljanovic, Natasa ^{[1
,3
,5
]}

Cmiljanovic, Vladimir ^{[1
,3
,5
]}

Bohnacker, Thomas ^{[1
]}

Melone, Anna ^{[1
]}

Marone, Romina ^{[1
]}

Jackson, Eileen ^{[1
]}

Zhang, Xuxiao ^{[2
]}

Sele, Alexander ^{[1
]}

Borsari, Chiara ^{[1
]}

Mestan, Jurgen ^{[3
]}

Hebeisen, Paul ^{[3
]}

Hillmann, Petra ^{[3
]}

Giese, Bernd ^{[4
,6
]}

Zvelebil, Marketa ^{[1
]}

Fabbro, Doriano ^{[3
]}

Williams, Roger L. ^{[2
]}

Rageot, Denise ^{[1
]}

Wymann, Matthias P. ^{[1
]}

机构：

[1] Univ Basel, Dept Biomed, Mattenstr 28, CH-4058 Basel, Switzerland

[2] MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England

[3] PIQUR Therapeut AG, Hochbergerstr 60C, CH-4057 Basel, Switzerland

[4] Univ Basel, Dept Chem, St Johanns Ring 19, CH-4056 Basel, Switzerland

[5] PIQUR Therapeut AG, Basel, Switzerland

[6] Univ Fribourg, Dept Chem, Fribourg, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 17期

基金：

瑞士国家科学基金会;

关键词：

PHOSPHOINOSITIDE; 3-KINASE; KINASE INHIBITOR; RAPAMYCIN INHIBITORS; PI3K INHIBITOR; CANCER; IDENTIFICATION; WORTMANNIN; TARGET; MTOR; NVP-BKM120;

D O I：

10.1021/acs.jmedchem.7b00930

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：7524 / 7538

页数：15

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