An orally active dual CBP/p300 degrader targets core dependencies of multiple myeloma [ATAC-seq]

The enhancer lysine acetyltransferases CBP and p300 are compelling targets for multiple myeloma therapy. Chemical inhibition of these multidomain factors, either through the bromodomain or the catalytic acetyltransferase domain, show promising activity in pre-clinical models of myeloma and other cancers. Some compounds, including the CBP/p300 bromodomain inhibitor inobrodib, have progressed to early-stage clinical trials. Chemical degradation of CBP/p300 is the only modality that can completely disrupt all functional domains of CBP and p300. Our previous attempts to induce CBP/p300 targeted degradation led to dCBP-1, a potent tool compound that induces degradation of both CBP and p300 by hijacking the activity of the E3 ligase CRBN. Here we comprehensively demonstrate across a large panel of cell lines how CBP/p300 degradation compares to inhibition, with pronounced selective antiproliferative activity towards multiple myeloma cells. We use chemical linker optimization strategies to create a compound with better pharmacokinetic properties to enable use in animal models. Through these efforts we define an advanced analog of dCBP-1, dCBP-30, that has improved potency in vitro, along with improved in vivo properties including oral bioavailability. dCBP-30 led to potent and sustained loss of CBP and p300 in myeloma cell lines, potent inhibition of several myeloma-specific dependency programs, and elicits tumor reduction in xenograft models as a single agent and in combination with dexamethasone when delivered orally.