Abstract 402: BCL6 degrader with novel CRBN ligand demonstrates promising selectivity and preclinical efficacy alone or in combination with BCL2 inhibitor

Abstract The B-cell lymphoma 6 (BCL6) transcription repressor, a protooncogene particularly significant in diffuse large B-cell lymphoma (DLBCL), is known to confer survival, protection, and maintenance of lymphoma cells. Its expression in normal B cells is crucial for the initiation and sustenance of germinal centers (GC). Somatic mutations of the BCL6 gene, including chromosomal translocations, have been linked to the deregulation of BCL6 expression, contributing to a subset of aggressive double- and triple-hit lymphomas with poor outcomes with conventional therapy. Addressing this critical clinical need, we have developed HSK47977, a highly specific, potent, and orally bioavailable BCL6 protein degrader with a novel CRBN ligand. Unlike traditional IMiDs, this new CRBN ligand alone had no IMiD activity and barely induced protein degradation in PBMC cells. Meanwhile, HSK47977 baring this ligand has shown remarkable in vitro and in vivo efficacy across multiple pre-clinical DLBCL models. HSK47977 achieves over 90% BCL6 degradation at 10 nM and a DC50 of less than 1 nM in the OCI-Ly1 model. Time-course studies revealed that over 90% BCL6 degradation was achieved within 1 hour and sustained up to 24 hours. Meanwhile, HSK47977 minimally induced the degradation of first-generation IMIDs targets, including GSPT1, SALL4, CK1α, Aiolos, and Ikaros, suggesting its safety profile. The optimization of the CRBN ligand has also significantly bolstered the pharmacokinetic (PK) profile of HSK47977, endowing it with impressive oral bioavailability and enhanced in vivo exposure following oral administration. In addition to this, we have devised a mechanism-based combination strategy aimed at amplifying the therapeutic potency of HSK47977. Given that BCL6 functions as a transcriptional repressor, the degradation of BCL6 could potentially upregulate the expression of the anti-apoptotic protein BCL2, providing the rational for combined inhibition of both. Indeed, we proved that the synergistic effects of of HSK47977 and a BCL2 inhibitor was achieved in both in vitro and in vivo. This combination therapy demonstrated that a minimal dose of HSK47977, when paired with a BCL2 inhibitor, was adequate to elicit tumor regression in CDX models. In summary, these findings underscore HSK47977 as a potent and orally bioavailable BCL6 degrader, distinguished by its novel CRBN ligand. Moreover, the strategic combination with a BCL2 inhibitor is poised to significantly augment the therapeutic efficacy, offering a promising approach for the treatment of diffuse large B-cell lymphoma. Citation Format: Jun Xu, Yangguang Li, Ju Wang, Pingmin Tang, Yuting Liao, Chen Zhang, Pangke Yan. BCL6 degrader with novel CRBN ligand demonstrates promising selectivity and preclinical efficacy alone or in combination with BCL2 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 402.