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Abstract

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 <b>1</b> (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 <b>1</b> in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, <b>1</b> did not bind tubulin, which was observed for the structurally related <b>4</b> (BKM120, buparlisib). Compound <b>1</b> is orally available, crosses the blood–brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound <b>1</b> demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound’s safety profile, identifies <b>1</b> as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound <b>1</b> is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma

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The Francis Crick Institute

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Last time updated on 12/02/2018

This paper was published in The Francis Crick Institute.

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