LY4584180，一种新型BCL6分子胶，在B细胞NHL的临床前模型中展现出抗肿瘤疗效

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<0.001), including tumor regression at multiple dose levels, with no significant body weight loss. These results demonstrate the ability of LY4584180 to selectively degrade BCL6, exert antiproliferative effects across a panel of malignant human B-cell lines, and exhibit antitumor activity in vivo . These findings suggest that LY4584180 has the potential to be effective in patients with hematologic malignancies. NOVA-BCL6-1, a phase 1 clinical trial evaluating LY4584180 in patients with NHL is currently enrolling (NCT07226843). 1 Xu J, et al. Cancer Res 2024, 84: Abstract 6062 2 Liongue C, et al. Int J Mol Sci 2024, 25:10968 3 Groocock L, et al. Blood 2024; 144 (Supplement 1): 957