Bimiralisib (PQR309) (C09-0785-912)

InformationBimiralisib (PQR309) is a novel brain-penetrant dualPI3K/mTORinhibitor with in vitro and in vivo antilymphoma activity. It displays excellent selectivity versus PI3K-related lipid kinases, protein kinases and unrelated targets.TargetsPI3Kα (Cell-free assay); PI3Kβ (Cell-free assay); mTOR (Cell-free assay); PI3Kγ (Cell-free assay); PI3Kδ (Cell-free assay) 1.5 nM(Kd); 11 nM(Kd); 12 nM(Kd); 25 nM(Kd); 25 nM(Kd)In vitroPQR309 shows in vitro activity with a median IC50 value of 233 nmol/L (95% CI, 174-324 nmol/L) in most of the tesed lymphoma cell lines (increasing doses, 72 hours). The arrest in proliferation is mainly due to cell cycle arrest with a block in G1 rather than to apoptosis, limited to only 2/7 cell lines. PQR309 is more active in B-cell lymphoma cell lines (DLBCL, MCL, CLL, and SMZL) than in the T-cell derived ALCL. PQR309 inhibits PI3K/mTOR signaling in lymphoma cell lines. It has in vitro and in vivo antilymphoma activity as single agent and in combination./xa0In vivoPQR309 is orally available, crosses the blood−brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. It shows little clearance when exposed to rat, dog, and human liver microsomes, with a quicker turnover of PQR309 in mouse liver microsomes, where 40% of the compound was eliminated within 30 min. In female mice, plasma concentrations of PQR309 depended on the drug administration route, resulting in half-lives of approximately 13-36 min for po administration vs 9-10 min for iv administration. PQR309 shows excellent oral bioavailability (>50%). Male Beagle dogs, exposed to PQR309 at 10 mg/kg po, showed maximal drug plasma concentrations Cmax of 583 ng/mL (approximately 1.5 μM) after 60-90 min and a half-life of >7 h, which results in drug levels of approximately 0.38 μM (150 ng/mL) after 24 h. The oral bioavailability in male Beagle dogs was estimated to be 23%. Altogether the PK studies in the three models (female CD-1 mouse, female Sprague-Dawley rats, male Beagle dog) show rapid absorption of PQR309 and good oral bioavailability. PQR309 demonstrates efficiency in inhibiting proliferation in tumor cell lines (PC3 prostate cancer cells) and a rat xenograft model (PC3 xenograft model).Cell Research(from reference)Cell lines：lymphoma cell lines Concentrations：500 nmol/L Incubation Time：72 h. Specifications and Purity: 98%. Molecular Formula: C17H20F3N7O2. Molecular Weight: 411.38. PubChem CID: 58507717. Isomeric SMILES: C1COCCN1C2=NC(=NC(=N2)C3=CN=C(C=C3C(F)(F)F)N)N4CCOCC4.