Bimiralisib

1225037-39-7

C17H20F3N7O2

DMSO : >= 50 mg/mL (121.54 mM)

PI3K/Akt/mTOR; PI3K/Akt/mTOR

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 PI3Kalpha, PI3Kdelta, PI3Kbeta, PI3Kgamma and mTOR, respectively. Bimiralisib is an mTORC1 and mTORC2 inhibitor. IC50 & Target: IC50: 33 nM (PI3Kalpha), 451 nM (PI3Kdelta), 661 nM (PI3Kbeta), 708 nM (PI3Kgamma), 36 nM (PI3Kalpha-H1047R), 63 nM (PI3Kalpha-E542K), 136 nM (PI3Kalpha-E545K), 89 nM (mTOR), 8486 nM (VPS34), 8567 nM (DNAPK)^[1] Kd: 1.5 nM (PI3Kalpha), 11 nM (PI3Kbeta), 25 nM (PI3Kdelta), 25 nM (PI3Kgamma), 12 nM (mTOR), 230 nM (VPS34), 850 nM (PI3KC2beta), 40000 nM (PI4KCbeta), 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 PI3Kalpha-H1047R), PI3Kalpha-E542K and PI3Kalpha-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. In mice, both po and iv application routes show a rapid drop below 200 ng/mL (ca.0.5 uM) 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 C_max. 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 uM (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].