PLX048190

GSE138209: Selective therapeutic targeting of the first and second bromodomains of the BET proteins in cancer and immuno-inflammation [SLAM-seq]

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

The evolutionarily conserved BET bromodomain family contain a distinctive tandem bromodomain structure that enables their chromatin binding to facilitate transcription. Whilst first-in-class drugsthat equally inhibit both bromodomains have shown pre-clinicaland clinical efficacy in a range of malignant and inflammatory pathologies, the functional contribution of the first (BD1) and second (BD2) bromodomains to these pathologies remains largely unknown. Here we haveexploited detailedstructuralinsights and our extensivemedicinal chemistry capabilities to develop novel compounds that are exquisitely selectivefor either BD1 or BD2 of the BET proteins. Using thesewell characterised domain-specific inhibitors we show that BD1 is required by all BET proteins to associate with chromatin and maintain established malignant transcriptional programs.Therefore, targeting BD1 alone phenocopies the therapeutic effects of current non-selective BET inhibitorsin models of cancer. Whilst steady state gene expression primarily requires BD1,we find that the rapid increase of gene expression effectedby a wide range of inflammatory stimuli requiresboth BD1 and BD2. Moreover, although BRD4 is the principal member required for the maintenance of established gene expression, efficient gene induction also requires BRD2 and BRD3. Selective inhibition of BD2 is effective in perturbing the recruitment of all the BET proteins for stimulated gene expression and consequently small molecule inhibitors of BD2 amelioratethe immunoinflammatory end organ damage seen in models of inflammatory arthritis, psoriasis and hepatitis. Together,these data provide novel biological and functional insights into this family of key transcriptional regulators. Importantly, they also help refine the future therapeutic approach when targeting the BET proteinsin distinct pathologies such as cancer and immuno-inflammation. SOURCE: Mark Dawson (mark.dawson@petermac.org) - Peter MacCallum Cancer Centre