Paxalisib (GDC-0084) is a PI3K and mTOR inhibitor that can penetrate the blood-brain barrier. It inhibits PI3Kα,PI3Kβ,PI3Kδ,PI3Kγ and mTOR with Ki values of 2 nM,46 nM,3 nM,10 nM and 70 nM respectively.
In vitro study
In microsomal and stem cell cultures, GDC-0084 has good human metabolic stability and can inhibit the key signal pAKT in the PI3K pathway in normal brain tissue. GDC-0084 inhibit the proliferation of a variety of glioma cells, the IC50 range is 0.3-1.1 μm. The binding rate of GDC-0084 to plasma protein is relatively low, and the free fraction in CD-1 mouse plasma is 29.5±2.7(%,n = 3,5 μm), the binding rate to brain tissue was higher in CD-1 mice, with a free fraction of 6.7%(± 1; n = 3).
In vivo study
In the mouse brain, GDC-0084 significantly inhibited the PI3K signaling pathway, resulting in up to 90% inhibition of pAkt signaling. GDC-0084 inhibited tumor growth by 70% and 40% in U87 and GS2 orthotopic xenograft models, respectively. Its widespread distribution in brain and intracranial tumors makes it a very effective inhibitor of the PI3K signaling pathway. At present, the efficacy of GDC-0084 is being evaluated in clinical patients, and the tolerated dose of exposure is consistent with the effective dose in mouse models.
