Activity of Orally Available CBP/p300 Degraders in Pre-Clinical Models of Multiple Myeloma

The enhancer lysine acetyltransferases CBP and p300 are compelling targets for therapy in multiple myeloma. Chemical inhibition of these 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 inobrodib, have progressed to early-stage clinical trials. Yet CBP/p300 inhibitors may only have partial effects on protein activity. Using heterobifunctional chemical approaches to induce targeted protein degradation we have developed dCBP-1, a potent tool compound that induces complete degradation of both CBP and p300 via hijacking the activity of the E3 ligase CRBN. This compound shows promising effects in myeloma cell lines with induction of apoptosis occurring in some lines within 48-72 hours of treatment. Tested across >300 cancer cell lines, myeloma cells are among the most sensitive to dCBP-1 treatment, and this activity is more pronounced when compared to CBP/p300 inhibitors. These antimyeloma effects are at least in part a consequence of rapid disruption of oncogenic transcriptional signaling networks mediated by essential transcription factors IRF4 and MYC. Yet dCBP-1 fails to achieve adequate exposures in mice to use as an in vivo tool. We have thus embarked on a chemical optimization strategy to incorporate newer heterobifunctional design strategies to create a compound with better pharmacokinetic properties for use in animal models. Our strategy included derivatization of the CRBN-binding moiety and progressive linker optimization. Through these efforts we have defined several advanced analogs of dCBP-1 that have dramatically improved potency in vitro, along with improved in vivo properties including oral bioavailability. With intermittent dosing strategies, advanced compounds lead to potent and sustained loss of CBP and p300 in myeloma cell lines and tumor xenografts and achieve tumor reduction as single agents when delivered orally. With these optimized compounds, we can now address systematically (in vitro and in vivo) the relative consequences of CBP/p300 inhibition and degradation both in tumor cells and normal tissue/hematopoietic cells.