p300 catalytic inhibition selectively targets IRF4 oncogenic activity in multiple myeloma (MM1S_KB528_timeseries)

The oncogenic transcription factor (TF) IRF4 is a universal multiple myeloma (MM) dependency that remains undrugged owing to its disordered structure. Using transcriptional regulatory network (TRN) mapping, an unbiased multi-omic approach to nominate druggable TF cofactors, we identified the chromatin coactivator lysine acetyltransferase (KAT) p300 as a key IRF4 partner. We developed KB528, a highly selective p300 KAT inhibitor to explore the regulatory relationship between IRF4 and p300. Instead of broadly inhibiting transcription, partial p300 KAT inhibition selectively downregulates IRF4 and its downstream gene expression program leading to apoptosis selectively in MM cells. IRF4 dependency is a hallmark of MM that exists downstream of existing MM therapies. Consequently, p300 KAT inhibition exhibits strong antiproliferative activity ex vivo and in vivo as a single agent as well as in combination regimens in treatment refractory models. p300 KAT inhibition is well-tolerated in vivo motivating further clinical development in MM.