HIF-1a is a heterodimerically-activated transcription factor central to the cellular response in hypoxic environments, often upregulated in cancer. Binding of HIF-1a to the coactivator p300 is necessary for the hypoxia-induced transcription of many oncogenic proteins. We investigated the inhibition of the HIF-1a-p300 interaction using two complementary approaches; high throughput screening (HTS) and rational drug design.To find selective inhibitors for this interaction, we analyzed results from a natural product HTS conducted by the NIH. Two structural units were prevalent � benzoquinones and 2-substituted indandiones. Synthetic derivatives of the hit compounds revealed that potency is closely correlated with their electrophilicity. Further work confirmed that the activity of these compound classes results from the reactivity of the functional groups which covalently modify p300, disrupting its fold, and ejecting structural Zn(ii) atoms.Following this work, we investigated non-covalent inhibitors of the HIF-1a/p300 interaction. Inhibition by peptide truncates guided the rational design of several a-helix peptidomimetic scaffolds to imitate the HIF-1a C-TAD domain helix, with hits showing modest activity (IC50= 200-500 �M).We now hope to harness the activity of the covalent binding compounds by coupling electrophiles to selective, rationally designed, non-covalent HIF-1a/p300 inhibitors. This combined approach may yield covalent inhibitors that retain the potency of the zinc ejecting species, while also increasing their specificity and therapeutic utility.

Synthetic modulation of the hypoxic response in cancer through inhibition of the HIF-1a/p300 protein-protein interaction

248th National Meeting (2014)

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