Development of small molecules to target KDM4B

摘要

ABSTRACT Epigenetic modifications of histone proteins play key roles in regulating transcription, and dysregulation of the epigenetic machinery has emerged as important driver of cancer initiation and progression. Histone lysine methylation is an important epigenetic mark that is dynamically regulated by histone methyltransferase `writers' and histone lysine demethylase `erasers' (KDMs). The KDMs comprise two structurally and mechanistically distinct classes of enzymes, and there is firm evidence that KDM4B in the larger Jumonji C (JmjC) class has a particularly key role in several cancers including breast and prostate cancer, acute myeloid leukemia and neuroblastoma. Published and ongoing studies from our group support the importance of KDM4B in breast cancer and neuroblastoma. These results have prompted us to initiate screening, cell biology and structural biology efforts to identify specific inhibitors of KDM4B. Two key findings from our studies provide a proof-of-concept that targeting KDM4B is a potentially valuable therapeutic option in cancer treatment. First, N-Myc recruits KDM4B to maintain low levels of repressive H3K9me2/me3 at Myc-binding sites and promotes neuroblastoma growth. Second, the small molecule ciclopirox inhibits KDM4B activity, suppresses the N-Myc pathway and reduces neuroblastoma growth. The immediate goal of this proposal within the scope of this FOA is to develop novel and potent inhibitors of KDM4B that display specificity within the JmjC class of KDMs. Such inhibitors can then be used to develop competent in vivo chemical probes to study the roles of KDM4B and other members of the KDM family in relevant preclinical cancer models. A longer term goal is to develop small molecule cancer therapies that target KDM4B. Previous biochemical and structural biology studies have thoroughly characterized the catalytic mechanism and substrate specificities of these enzymes, and this information will fully exploited as we proceed. Four laboratories with diverse expertise have and will continue to collaborate on this project: Drs. Jun Yang and Andrew Davidoff (hit validation), Dr. Taosheng Chen (screening), and Dr. Stephen White (biophysical studies and structural biology). In addition, Dr. Zoran Rankovic will provide medicinal chemistry expertise that will be increasingly important as we move towards therapeutic development. As defined within the FOA, the project includes 3 stages: assay development (Stage 1), primary screen implementation (Stage 2) and hit validation (Stage 3). Stages 1 and 2 are well advanced and the emphasis will therefore be on Stage 3.