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Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl–Pyrimidine Moiety
- 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.
- Subjects :
- Letter
Pyrimidine
Regulator
01 natural sciences
Biochemistry
mammalian or mechanistic target of rapamycin (mTOR)
PI3K inhibitor
chemistry.chemical_compound
Pharmacokinetics
Drug Discovery
Potency
4-(difluoromethyl)pyrimidin-2-amine
Mechanistic target of rapamycin
PI3K/AKT/mTOR pathway
biology
010405 organic chemistry
Cell growth
Phosphoinositide 3-kinase (PI3K)
Organic Chemistry
clinical candidate
In vitro
0104 chemical sciences
010404 medicinal & biomolecular chemistry
chemistry
cancer
ATP-competitive
pharmacology
biology.protein
Cancer research
Subjects
Details
- ISSN :
- 19485875
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- ACS Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....140ec0b3faa4fa9ba554a9871c8b8f1c