Description
Bimiralisib is a potent and orally bioavailable inhibitor of phosphatidylinositol 3-kinases (PI3Ks; IC
50s = 33, 661, 708, and 451 nM for PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ, respectively) and the mammalian target of rapamycin (mTOR; IC
50 = 89 nM). It is selective for these kinases over a panel of cell surface and nuclear receptors, membrane channels, transporters, kinases, proteases, and phosphodiesterases at a concentration of 10 μM. Bimiralisib has anticancer activity with an average GI
50 value of 0.7 μM across the National Cancer Institute (NCI) 60 human cancer cell line panel.
In vivo, bimiralisib (5-15 mg/kg) reduces tumor growth in a dose-dependent manner in a PC3 prostate cancer mouse xenograft model. Formulations containing bimiralisib are under clinical investigation for the treatment of relapsed and refractory lymphoma and advanced solid tumors.
in vivo
Oral administration yields similar concentrations of Bimiralisib in brain and plasma samples illustrates that Bimiralisib readily passes the blood–brain barrier. In mice, both po and iv application routes show a rapid drop below 200 ng/mL (~0.5 μM) of PQR309 within <1 h (iv) to <2 h (po) after administration, which reflects the time point when the drug reaches the median GI50 determined in tumor cell lines. In female rats a single oral dose (10 mg/kg) achieves similar drug levels as a single intravenous injection (5 mg/kg) with regard to Cmax. The half-life of 5-8 h and an AUC0.25-12 of around 14 000 hng/mL contributed to an excellent oral bioavailability of PQR309 (>50%). Twenty-four hours after po administration, plasma levels of PQR309 are still >2 μM (800-1000 ng/mL). Moreover, after 1-2 h exposure to PQR309 , drug levels in rat brain samples are comparable to plasma levels, confirming rapid access of PQR309 to the brain[1].
IC 50
PI3Kα: 33 nM (IC
50); PI3Kα-H1047R: 36 nM (IC
50); PI3Kα-E542K: 63 nM (IC
50); PI3Kα-E545K: 136 nM (IC
50); PI3Kδ: 451 nM (IC
50); PI3Kβ: 661 nM (IC
50); PI3Kγ: 708 nM (IC
50); Vps34: 6486 nM (IC
50); mTOR: 89 nM (IC
50); mTORC1; mTORC2; DNA-PK: 8567 nM (IC
50)
References
[1] FLORENT BEAUFILS. 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology[J]. Journal of Medicinal Chemistry, 2017, 60 17: 7524-7538. DOI:
10.1021/acs.jmedchem.7b00930
