Abstract 4594: LY4584180, a novel BCL6 molecular glue, demonstrates antitumor efficacy in preclinical models of B Cell NHL

Abstract B-cell lymphoma 6 (BCL6) is a protooncogene and key molecular driver of DLBCL, FL, and other B-cell malignancies. BCL6 gene alterations such as chromosomal translocations or somatic mutations, lead to deregulation of BCL6 expression, contributing to poorly prognostic double- and triple-hit lymphomas.1 Given its role in repressing genes involved in DNA damage response, cell cycle checkpoints, and differentiation,2 BCL6 is a promising drug target for the treatment of non-Hodgkin Lymphomas (NHL). Small molecule inhibitors have been ineffective in disrupting BCL6-mediated oncogenic activity; emerging evidence suggests that degradation of BCL6 is essential for antitumor activity.3 Here, we describe the characterization of LY4584180, an oral, highly selective, small molecule BCL6 molecular glue. LY4584180 induces BCL6 homodimerization at the BTB/POZ domain, resulting in BCL6 polymers sequestered into cellular aggregates, leading to polyubiquitination of the BCL6 aggregates by E3 ligases, and subsequent degradation by the proteasome. The unique non-cereblon dependent degradation mechanism allows combination with IMiDs and may also reduce a key mechanism for on-target drug resistance, in comparison to other ligand directed cereblon degraders. LY4584180 has demonstrated rapid, potent, and concentration-dependent degradation of BCL6 protein in both transcriptionally defined DLBCL subtypes, activated B-cell (ABC; OCI-Ly10) and germinal center B-cell (GCB; Farage and SU-DHL-4). DC50 (concentration of LY4584180 resulting in 50% degradation of BCL6) values ranged from 1 to 22 nM at 24 hrs with maximal degradation (∼96-97%) observed within 2 hrs, as quantified by Mesoscale Diagnostics ELISA. Furthermore, LY4584180 demonstrated anti-proliferative activity across a panel of human NHL cell lines with mid- to high-BCL6 expression, including ABC and GCB DLBCL subtypes. Additionally, in a mass spectrometry-based proteomics study using SU-DHL-4 cells, the compound selectively reduced BCL6 relative to its effects on the global proteome. In DLBCL cell line-derived xenograft models, LY4584180 demonstrated robust dose-dependent BCL6 degradation and antitumor activity (p