( 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.
Denise Rageot  1 ,  Thomas Bohnacker  1 ,  Erhan Keles  1 ,  Jacob A McPhail  2 ,  Reece M Hoffmann  2 ,  Anna Melone  1 ,  Chiara Borsari  1 ,  Rohitha Sriramaratnam  1 ,  Alexander M Sele  1 ,  Florent Beaufils  1 ,  Paul Hebeisen  3 ,  Doriano Fabbro  3 ,  Petra Hillmann  3 ,  John E Burke  2 ,  Matthias P Wymann  1
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.

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