(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

Denise Rageot; Thomas Bohnacker; Erhan Keles; Jacob A McPhail; Reece M Hoffmann; Anna Melone; Chiara Borsari; Rohitha Sriramaratnam; Alexander M Sele; Florent Beaufils; Paul Hebeisen; Doriano Fabbro; Petra Hillmann; John E Burke; Matthias P Wymann

doi:10.1021/acs.jmedchem.9b00525

(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. 2019 Jul 11;62(13):6241-6261. doi: 10.1021/acs.jmedchem.9b00525. Epub 2019 Jun 20.

Authors

Affiliations

¹ Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.
² Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.
³ PIQUR Therapeutics AG , Hochbergerstrasse 60C , 4057 Basel , Switzerland.

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

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines / chemical synthesis
Aminopyridines / metabolism
Aminopyridines / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Brain / metabolism
Cell Line, Tumor
Dogs
Female
Humans
Male
Mice, Inbred BALB C
Mice, Inbred C57BL
Microsomes, Liver / metabolism
Molecular Docking Simulation
Molecular Structure
Morpholines / chemical synthesis
Morpholines / metabolism
Morpholines / pharmacology*
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors / chemical synthesis
Phosphoinositide-3 Kinase Inhibitors / metabolism
Phosphoinositide-3 Kinase Inhibitors / pharmacology*
Protein Binding
Pyridines / chemical synthesis
Pyridines / metabolism
Pyridines / pharmacology*
Rats, Wistar
Structure-Activity Relationship
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism
Triazines / chemical synthesis
Triazines / metabolism
Triazines / pharmacology*
Xenograft Model Antitumor Assays

Substances

Aminopyridines
Antineoplastic Agents
Morpholines
PQR530
Phosphoinositide-3 Kinase Inhibitors
Pyridines
Triazines
MTOR protein, human
TOR Serine-Threonine Kinases