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Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl–Pyrimidine Moiety

Authors :
Chiara Borsari
Doriano Fabbro
Petra Hillmann
Florent Beaufils
Thomas Bohnacker
Matthias P. Wymann
Denise Rageot
Ivan Buslov
Erhan Keles
Alexander M. Sele
Anna Melone
Paul Hebeisen
Source :
ACS Medicinal Chemistry Letters
Publication Year :
2019
Publisher :
American Chemical Society (ACS), 2019.

Abstract

The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is a critical regulator of cell growth and is frequently hyperactivated in cancer. Therefore, PI3K inhibitors represent a valuable asset in cancer therapy. Herein we have developed a novel anticancer agent, the potent pan-PI3K inhibitor PQR514 (4), which is a follow-up compound for the phase-II clinical compound PQR309 (1). Compound 4 has an improved potency both in vitro and in cellular assays with respect to its predecessor compounds. It shows superiority in the suppression of cancer cell proliferation and demonstrates significant antitumor activity in an OVCAR-3 xenograft model at concentrations approximately eight times lower than PQR309 (1). The favorable pharmacokinetic profile and a minimal brain penetration promote PQR514 (4) as an optimized candidate for the treatment of systemic tumors.

Details

ISSN :
19485875
Volume :
10
Database :
OpenAIRE
Journal :
ACS Medicinal Chemistry Letters
Accession number :
edsair.doi.dedup.....140ec0b3faa4fa9ba554a9871c8b8f1c