CDK4 and CDK6 are validated targets in HR+ breast cancers. Approved CDK4/6 inhibitors have limited utility in breast cancers with brain metastases and other central nervous system (CNS) cancers, including glioblastoma multiforme (GBM). PRT3645 is a highly potent, selective and brain penetrant CDK4/6 inhibitor that demonstrated greater than 10x brain penetration compared to approved CDK4/6 agents in preclinical models. Prelude intends to develop PRT3645 in these underserved cancers.
Given the central roles that CDK4 and CDK6 play in cell cycle regulation, dysregulation of the CDK4/CDK6 pathway has been frequently observed in cancer and CDK4/CDK6 have been intensively investigated as potential therapeutic targets for cancer treatment. The approval of three CDK4/CDK6 selective inhibitors in combination with endocrine therapies, to treat hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer has further validated this hypothesis.
Despite the success of CDK4/CDK6 inhibitors for the treatment of ER+ metastatic breast cancer, central nervous system (CNS) diseases such as glioblastoma (GBM) and brain metastases remains challenging and represent malignancies with urgent unmet needs. Large scale genomic studies revealed that the CDK4/CDK6 pathway is disrupted in the majority of gliomas, suggesting CDK4/CDK6 may be good targets for GBM. In addition, brain metastases may arise in an estimated 20% of all cancer patients but still lacks effective therapies. Genomic studies also identified the CDK4/6 pathway as one of three most altered and actionable genetic alternations in brain metastasis. However, despite positive preclinical data supporting targeting CDK4/CDK6 to treat CNS cancers, clinical development of CDK4/CDK6 inhibitors for GBM or brain metastases has not been successful, likely due to the inability of current inhibitors to penetrate the blood-brain barrier (BBB) and achieve effective concentrations in the brain.
PRT3645 is Prelude’s novel, highly brain penetrant molecule that potently and selectively targets CDK4/6. In preclinical studies, PRT3645 treatment results in concentration-dependent inhibition of cell proliferation in glioblastoma (GBM) cell lines and in ER+/HER2- and HER2+ breast cancer lines. In vivo, orally administered PRT3645 was well tolerated and highly efficacious in a dose-dependent manner in orthotopic human breast cancer brain metastasis and GBM models. In a head to head comparison, PRT3645 demonstrated a brain:plasma ratio that was ~100x higher than approved CDK4/6 inhibitors. A Phase 1 clinical trial is being initiated for PRT3645 and includes sarcomas, P16 mutated mesothelioma, gliomas, HPV negative head and neck cancers and CDK pathway-altered non-small cell lung cancer, in addition to HR+/HER2+ and HR+/HER2- breast cancer with or without brain metastases.