Paxalisib (GDC-0084) (C007B-248478)

InformationPaxalisib (GDC-0084, RG7666) is a brain penetrant inhibitor ofPI3KandmTORwith Kiapp values of 2 nM, 46 nM, 3 nM, 10 nM and 70 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ and mTOR.TargetsPI3Kα (Cell-free assay); PI3Kδ (Cell-free assay); PI3Kγ (Cell-free assay); PI3Kβ (Cell-free assay); mTOR (Cell-free assay) 2 nM(Ki app); 3 nM(Ki app); 10 nM(Ki app); 46 nM(Ki app); 70 nM(Ki app)In vitroGDC-0084 has excellent human metabolic stability in microsomal and hepatocyte incubations and demonstrated inhibition of pAKT, a key signal within the PI3K pathway, in normal brain tissue. GDC-0084 is shown to inhibit the proliferation of several glioma cells in vitro with IC50 ranging from 0.3 to 1.1 μM. GDC-0084 binding to plasma proteins is low, with a free fraction (%) of 29.5±2.7 (n=3) in CD-1 mouse plasma, when tested at 5 μM. Binding to brain tissues from CD-1 mice is higher, with a free fraction of 6.7% (±1; n=3).In vivoGDC-0084 markedly inhibits the PI3K pathway in mouse brain, causing up to 90% suppression of the pAkt signal. GDC-0084 achieves significant tumor growth inhibition of 70% and 40% against the U87 and GS2 orthotopic models, respectively. GDC-0084 distribution throughout the brain and intracranial tumors leads to potent inhibition of the PI3K pathway. It is being evaluated in patients, and exposures reached at tolerated doses are consistent with those associated with efficacious doses in mouse models.Cell Research(from reference)Cell lines：Madin-Darby canine kidney (MDCK) cells （MDR1-MDCKI cells） Concentrations：5 μM Incubation Time：2 h. Specification: 0.99 Molecular Formula: C18H22N8O2 Molecular Weight: 382.42 PubChem CID: 57384863 Isomeric SMILES: CC1(C2=NC3=C(N2CCO1)N=C(N=C3N4CCOCC4)C5=CN=C(N=C5)N)C Related Documents: https://ald-pub-files.oss-cn-shanghai.aliyuncs.com/aladdinsci/pdp/sds/1/P413923-SCI_b47e1021f0294f1dd31c16a6f340a483.pdf