6OAC

PQR530 [(S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine] bound to the PI3Ka catalytic subunit p110alpha

Summary for 6OAC

• Entry DOI: 10.2210/pdb6oac/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, 4-(difluoromethyl)-5-{4-[(3S)-3-methylmorpholin-4-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-yl}pyridin-2-amine (2 entities in total)
• Functional Keywords: pik3ca, mtor, phosphoinositide, pip3, pi3k, p110, signaling protein, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 110606.82

Authors

Burke, J.E.,McPhail, J.A. (deposition date: 2019-03-15, release date: 2019-06-26, Last modification date: 2023-10-11)

Primary citation

Rageot, D.,Bohnacker, T.,Keles, E.,McPhail, J.A.,Hoffmann, R.M.,Melone, A.,Borsari, C.,Sriramaratnam, R.,Sele, A.M.,Beaufils, F.,Hebeisen, P.,Fabbro, D.,Hillmann, P.,Burke, J.E.,Wymann, M.P.
(S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.
J.Med.Chem., 62:6241-6261, 2019

PubMed Abstract: 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: ()-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530, compound ), 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 showed excellent selectivity over a wide panel of kinases and an excellent selectivity against unrelated receptor enzymes and ion channels. Moreover, compound prevented cell growth in a cancer cell line panel. The preclinical in vivo characterization of compound in an OVCAR-3 xenograft model demonstrated good oral bioavailability, excellent brain penetration, and efficacy. Initial toxicity studies in rats and dogs qualify for further development as a therapeutic agent in oncology.

PubMed: 31244112
DOI: 10.1021/acs.jmedchem.9b00525

Experimental method

X-RAY DIFFRACTION (3.15 Å)