Abstract 6781: First in class catalytic inhibitor of KAT2A/B demonstrates anti-tumor activity in multiple myeloma

Abstract KAT2A/B are lysine acetyltransferases that function as catalytic members of the SAGA and ATAC protein complexes, which are lineage dependencies in several tumor types including multiple myeloma (MM). Here we describe a first-in-class, small molecule catalytic inhibitor targeting the lysine acetyltransferases KAT2A and KAT2B. KAT2 inhibition disrupts oncogenic transcriptional programs, including MYC and E2F pathways, leading to growth arrest in multiple myeloma. KAT2 catalytic inhibition reduces chromatin accessibility through the loss of H3K9ac and shows single-agent activity across a panel of MM cell lines. KAT2 inhibition demonstrates tumor growth inhibition as a monotherapy in both immune modulatory drug (IMiD) sensitive and resistant multiple myeloma tumor models with good correlation with reduction of H3K9ac in vivo. KAT2 inhibition has synergistic effects with IMiDs in vitro and demonstrates increased tumor growth inhibition in combination with pomalidomide and dexamethasone in vivo. Additionally, KAT2 inhibition enhances tumor immunogenicity by activating interferon regulatory factors (IRFs) and upregulating interferon-stimulated genes (ISGs). Using a syngeneic mouse model of MM, KAT2 inhibition alters the tumor microenvironment through increased infiltration of pro-inflammatory immune cells, resulting in tumor growth inhibition and enhanced survival in combination with a mBCMA-CD3 bispecific antibody. KAT2 catalytic inhibition represents a novel therapeutic approach targeting epigenetic regulation of tumor intrinsic and immune pathways in hematologic malignancies. Citation Format: Kristen Jensen-Pergakes, Shawn O'Connell, Sacha Ninkovic, Natalie Miller, Clifford Restaino, Alok Ranjan, Sara Linker, Dana J. Ramms, Hieu Lam, Allison Rohner, Parsa Alan, Ravi Visswanathan, Eric C. Greenwald, Patrick Shelton, Daniel Sandoval, Jacqui Hoffman, Joyann Donaldson, Gwenaella Rescourio, Keith Abayasiriwardana, Akshata Udyavar, Thomas A. Paul. First in class catalytic inhibitor of KAT2A/B demonstrates anti-tumor activity in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6781.