5OQ4

PQR309 - a Potent, Brain-Penetrant, Orally Bioavailable, pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

Summary for 5OQ4

• Entry DOI: 10.2210/pdb5oq4/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 5-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: pi3k, 3-kinase, lipid kinase, kinase, inhibitor, pqr309, ncb5, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P48736
• Total number of polymer chains: 1
• Total formula weight: 111359.67

Authors

Williams, R.L.,Zhang, X. (deposition date: 2017-08-10, release date: 2017-09-06, Last modification date: 2024-01-17)

Primary citation

Beaufils, F.,Cmiljanovic, N.,Cmiljanovic, V.,Bohnacker, T.,Melone, A.,Marone, R.,Jackson, E.,Zhang, X.,Sele, A.,Borsari, C.,Mestan, J.,Hebeisen, P.,Hillmann, P.,Giese, B.,Zvelebil, M.,Fabbro, D.,Williams, R.L.,Rageot, D.,Wymann, M.P.
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.
J. Med. Chem., 60:7524-7538, 2017

PubMed 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 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.

PubMed: 28829592
DOI: 10.1021/acs.jmedchem.7b00930

Experimental method

X-RAY DIFFRACTION (2.7 Å)