KB528

KB528 is a highly selective small molecule inhibitor of the lysine acetyltransferase (KAT) domain of p300 (EP300) and its close homolog CREB-binding protein (CBP). Developed by Kronos Bio, KB528 was designed to disrupt the oncogenic transcription regulatory network (TRN) driven by interferon regulatory factor 4 (IRF4), which is a critical dependency in multiple myeloma (MM). By partially inhibiting p300/CBP KAT activity, KB528 selectively downregulates IRF4 and its downstream gene expression program, leading to apoptosis in multiple myeloma cells while sparing normal cells. Preclinical studies have demonstrated that KB528 has robust antiproliferative activity in vitro, ex vivo, and in vivo, both as a single agent and in combination with standard-of-care therapies like immunomodulatory imide drugs (IMiDs) and dexamethasone. Optimization of KB528 led to the nomination of KB-9558 as a clinical development candidate.