Bimiralisib

Bimiralisib (PQR309) is a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor with IC₅₀s of 33 nM, 451 nM, 661 nM, 708 nM and 89 nM for PI3Kα, PI3Kδ, PI3Kβ, PI3Kγ and mTOR, respectively. Bimiralisib is an mTORC1 and mTORC2 inhibitor. IC50 & Target:IC50: 33 nM (PI3Kα), 451 nM (PI3Kδ), 661 nM (PI3Kβ), 708 nM (PI3Kγ), 36 nM (PI3Kα-H1047R), 63 nM (PI3Kα-E542K), 136 nM (PI3Kα-E545K), 89 nM (mTOR), 8486 nM (VPS34), 8567 nM (DNAPK)^[1] Kd: 1.5 nM (PI3Kα), 11 nM (PI3Kβ), 25 nM (PI3Kδ), 25 nM (PI3Kγ), 12 nM (mTOR), 230 nM (VPS34), 850 nM (PI3KC2β), 40000 nM (PI4KCβ), 1600 nM (DNAPK)^[1] mTORC1, mTORC2^[2] In Vitro:Bimiralisib is a highly selective pan-PI3K inhibitor with a balanced targeting of mTOR kinase. Bimiralisib also inhibits PI3Kα-H1047R), PI3Kα-E542K and PI3Kα-E545K with IC₅₀s of 36 nM, 63 nM and 136 nM, respectively^[1]. In Vivo:Oral administration yields similar concentrations of Bimiralisib in brain and plasma samples illustrates that Bimiralisib readily passes the blood-brain barrier^[1].
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^[1].
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 C_max^[1].
The half-life of 5-8 h and an AUC_0.25-12 of around 14 000 h ng/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].