Lysine histone demethylase 4C (KDM4C), a member of the 2-oxogluatrate and Fe (II) dependent dioxygenase family, plays a vital role in the regulation of chromatin remodeling processes. KDM4C catalyzes the removal of repressive H3K9me2/3 methyl marks and permissive H3K36me2/3 methyl marks on chromatin. However, the dysregulation and overexpression of KDM4C is implicated in a number of human pathologies, including cancers. In this report, we will describe the discovery of QC6352, a KDM4C inhibitor that is strongly anti-proliferative in cancer lines and efficacious in breast and colon PDX models. The alteration of H3K9me3 and H3K36me3 upon treatment with QC6352 was verified by Western blots and HTRF assays utilizing a KDM4C overexpressed cell line. Mass spectroscopy detection of post-translational modifications of global methyl marks will also be described.

Design of KDM4C inhibitors with antiproliferative effects in cancer models

255th National Meeting (2018)

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