A brain-penetrant CDK4/6 inhibitor - AU3-14 shows robust anti-tumor efficacy against glioblastoma

Abstract

The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in glioblastoma (GBM), the most aggressive and poorly prognosed brain malignancy. Despite extensive research, advances in GBM treatment have seen limited progress, with current therapy largely reliant on temozolomide (TMZ), underscoring the need for novel therapeutic strategies. This study explores the therapeutic potential of AU3–14, a potent and selective CDK4/6 inhibitor, for GBM. In CDK4-amplified GBM cell lines, AU3–14 significantly reduced phosphorylation of Rb and levels of cell cycle-related proteins, resulting in G₁/G₀ cell cycle arrest and senescence. Biopharmaceutical analysis indicated that AU3–14 has high membrane permeability and low P-glycoprotein substrate potential. More extensive pharmacokinetic studies revealed that AU3–14 efficiently crosses the blood-brain barrier, with an unbound brain-to-plasma concentration ratios (K_p,uu) of 1.2 and 0.63 at single oral doses of 10 and 30 mg/kg, respectively, which were 2–4 times higher than those of abemaciclib. In subcutaneous and orthotopic GBM mouse models, AU3–14 demonstrated substantial anti-tumor efficacy and safety. Further toxicokinetic studies in rats and cynomolgus monkeys following 28-day repeated doses demonstrated that AU3–14 is well-tolerated, with a low risk of hematological toxicities, such as neutropenia, which are commonly associated with other CDK4/6 inhibitors. Moreover, AU3–14 enhances TMZ’s anti-tumor efficacy and delays the onset of TMZ resistance. These findings support the clinical phase I/IIa investigation of AU3–14 for the treatment of GBM (ACTRN12621000479808).