Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl-Pyrimidine Moiety
Articolo
Data di Pubblicazione:
2019
Citazione:
Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl-Pyrimidine Moiety / C. Borsari, D. Rageot, F. Beaufils, T. Bohnacker, E. Keles, I. Buslov, A. Melone, A.M. Sele, P. Hebeisen, D. Fabbro, P. Hillmann, M.P. Wymann. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 10:10(2019 Oct 10), pp. 1473-1479. [10.1021/acsmedchemlett.9b00333]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
4-(difluoromethyl)pyrimidin-2-amine; cancer; ATP-competitive; pharmacology; clinical candidate; mammalian or mechanistic target of rapamycin (mTOR); PI3K inhibitor; Phosphoinositide 3-kinase (PI3K);
Elenco autori:
C. Borsari, D. Rageot, F. Beaufils, T. Bohnacker, E. Keles, I. Buslov, A. Melone, A.M. Sele, P. Hebeisen, D. Fabbro, P. Hillmann, M.P. Wymann
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