PQR309

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

PQR309 (Bimiralisib) 是一种有效的、脑渗透性、口服生物利用度、泛 I 类 PI3K/mTOR 抑制剂，对 PI3Kα、PI3Kδ、PI3Kβ、PI3Kγ 和 mTOR 的 IC50 分别为 33、451、661、708 和 89 nM。

PQR309 (Bimiralisib) is a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor with IC50 of 33, 451, 661, 708 and 89 nM for PI3Kα, PI3Kδ, PI3Kβ, PI3Kγ and mTOR, respectively; also shows potent activity against PI3Kα E542K/E545K/H2047R mutants with IC50 of 63/136/36 nM, shows no significant activity for VPS34 and DNA-PK (IC50>8,000 nM); inhibits cellular phosphorylation of PKB/Akt on Ser473 and ribosomal S6 on Ser235/236 in A2058 melanoma cells with IC50 of 139 and 205 nM, SKOV3 cell growth IC50 is 237 nM; demonstrates efficiency in inhibiting proliferation in tumor cell lines and rat xenograft models. Brain Cancer Phase 2 Clinical(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.(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 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.

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, 63nM and 136 nM, respectively.

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 PQR309within <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 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.

Bimiralisib | PQR-309 | PQR 309

PI3K/Akt/mTOR signaling

PI3K

pPKB|pS6

Cancer

Brain Cancer

1225037-39-7

411.3816

C17H20F3N7O2

>98% (HPLC)

10 mM in DMSO

C1COCCN1C2=NC(=NC(=N2)C3=CN=C(C=C3C(F)(F)F)N)N4CCOCC4

2-Pyridinamine, 5-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)-

(-20℃)

With Ice Pack

≥ 2 years