SMARCA2 and SMARCA4 (also known as BRM and BRG1, respectively) are involved in the regulation of gene expression through chromatin remodeling. SMARCA4 has been shown to be mutated in multiple cancers, including 10-12% of non-small cell lung cancer (NSCLC). Because the activity of either SMARCA2 or SMARCA4 is required for chromatin remodeling to occur, SMARCA4-deficient cancer cells become highly dependent on SMARCA2 for their survival. Targeting SMARCA2 in SMARCA4-deficient cancers is believed to produce a strong synthetic lethality, resulting in SMARCA4-mutant tumor cell death while sparing normal cells that express SMARCA4 protein. However, structural similarities between the two have historically posed challenges for selective SMARCA2 inhibition.
Prelude is developing highly potent and selective SMARCA2 protein degraders designed to specifically inhibit SMARCA4-deficient tumors. During 2022, Prelude intends to complete IND-enabling studies and submit an IND application by year-end.
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. Prelude plans to file an Investigational New Drug application and initiate a Phase 1 clinical trial of PRT3645 in the second half of 2022.