Exth-14. preclinical evaluation of novel cdk4/6 inhibitor glr2007 in glioblastoma models

Abstract Glioblastoma multiforme (GBM) is characterized by a high frequency of cyclin-dependent kinase (CDK)4 and CDK6 pathway dysregulation. None of the approved CDK4/6 inhibitors are indicated for GBM. Poor blood–brain barrier (BBB) penetration is a potential factor limiting treatment efficacy in GBM. GLR2007 is an investigational CDK4/6 inhibitor with the potential for improved penetration across the BBB. These preclinical studies investigated the anti-tumor efficacy in GBM xenograft models and central nervous system distribution of GLR2007. In vivo evaluation of the anti-tumor efficacy of GLR2007 versus vehicle, abemaciclib, and/or palbociclib was performed in two BALB/c nude mouse GBM xenograft models. Efficacy was expressed as tumor growth inhibition (TGI, change in mean tumor volume from baseline as a percentage of change in vehicle group) or increased survival time. Following 21 days of treatment, TGI in BN2289 subcutaneous xenografts was 39.4% and 56.4% for 25 mg/kg and 50 mg/kg GLR2007 groups, respectively, 34.0% for 25 mg/kg palbociclib, and 24.9% for 25 mg/kg abemaciclib (p < 0.001 in all groups vs vehicle control). In U87-luc orthotopic xenografts, compared with vehicle controls, median survival time was 50.0% (p = 0.0009) longer in the 12.5 mg/kg GLR2007 group, similar to the 150 mg/kg abemaciclib group (54.4%, p = 0.0002), and was 182.6% (p < 0.0001) longer in mice treated with 50 mg/kg GLR2007. Quantitative whole-body autoradiography was used to determine the distribution of [14C]GLR2007 in Sprague Dawley rats following a single oral dose. Total radioactivity levels in the brain exceeded those in plasma by 2.3–4.5-fold from 2–6 h after dosing. These preclinical studies suggest the potential of GLR2007 for the treatment of GBM, supported by evidence that GLR2007 showed numerically greater anti-tumor efficacy than approved CDK4/6 inhibitors palbociclib and abemaciclib in GBM xenograft models, and evidence of substantial central nervous system distribution.