PQR309

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 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.