Grant: Travel Awards - Institute Community Support

Recurrent histone methyltransferase gene mutations in cancer cells provide a mechanism for genome wide alterations in chromatin regulation. In lymphomas, the most frequently mutated methyltransferase is MLL2, which writes activatory histone marks mediated by the reader protein, BPTF. Loss of function mutations in MLL2 lead to a concomitant increase in H3K4me1 levels, which is predicted to lead to inappropriate transcriptional silencing in lymphoma cells. In this work, we have computationally developed compounds that reprogram the H3K4me3 reader BPTF to recognize and bind to other H3K4 forms via the formation of a triple complex of H3K4me1, BPTF and the compound. The compounds were initially screened in silico followed by in vitro assays in DLBCL cell lines. Those compounds that showed MLL2 mutant- specific activity were further subjected to pull- down assays which confirmed the reprogramming effects of the compounds by altering the stability of BPTF complexes with peptides in different methylated states of H3K4 residue. In our mouse xenograft model, these compounds had a significant effect on tumour growth. To the best of our knowledge, this is the first example of small molecules modulating epigenomic programming by creating an artificial regulatory pathway in cancer cells, compensating for the lack of MLL2 methyltransferase activity. We believe that the development of modulating compounds of epigenomic programs is innovative and provides a new paradigm for the development of epigenomic targeting drugs