Bimiralisib (PQR309) is a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor, Bimiralisib inhibits PI3Kα, PI3Kδ, PI3Kβ, PI3Kγ and mTOR with IC50s of 33 nM, 451 nM, 661 nM, 708 nM and 89 nM, respectively. PQR309 also inhibits PI3Kα-H1047R, PI3Kα-E542K and PI3Kα-E545K with IC50s of 36 nM, 63 nM and 136 nM, respectively. In vivo, 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 in mice, which reflects the time point when the compound 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.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: 10 mM|
First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with advanced solid tumors (SAKK 67/13).
Wicki A, et al. Eur J Cancer. 2018 Jun;96:6-16. PMID: 29660598.
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.
Beaufils F, et al. J Med Chem. 2017 Sep 14;60(17):7524-7538. PMID: 28829592.
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