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

Chiara Borsari; Denise Rageot; Florent Beaufils; Thomas Bohnacker; Erhan Keles; Ivan Buslov; Anna Melone; Alexander M Sele; Paul Hebeisen; Doriano Fabbro; Petra Hillmann; Matthias P Wymann

doi:10.1021/acsmedchemlett.9b00333

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

ACS Med Chem Lett. 2019 Sep 3;10(10):1473-1479. doi: 10.1021/acsmedchemlett.9b00333. eCollection 2019 Oct 10.

Affiliations

¹ Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
² PIQUR Therapeutics AG, Hochbergerstrasse 60, 4057 Basel, Switzerland.

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.