Orally bioavailable BCL6 degrader HSK47977 featuring a novel CRBN ligand demonstrates potent antitumor activity and synergy with BCL2 inhibition in NHL

The B‑cell lymphoma 6 (BCL6) transcriptional repressor is a proto‑oncogene pivotal in diffuse large B‑cell lymphoma (DLBCL) and follicular lymphoma (FL). In normal B cells, BCL6 is essential for germinal‑center (GC) initiation and maintenance. In DLBCL and FL, BCL6 is one of the most frequently genetically dysregulated proteins, leading to inhibited apoptosis and enhanced tumor proliferation. HSK47977 is an oral, highly selective, and potent BCL6 degrader that incorporates a novel cereblon (CRBN) ligand. In vitro, HSK47977 rapidly degrades BCL6 protein with a DC 50  < 1 nM in the OCI‑Ly1 cell line. Leveraging the unique CRBN ligand, HSK47977 exhibits markedly higher selectivity for BCL6 over other neo‑substrates. Proteomic profiling and subsequent Western‑blot analysis of five canonical IMiD targets (GSPT1, SALL4, CK1alpha, Aiolos, and Ikaros) confirm this superior selectivity. Optimization of the CRBN ligand also substantially improves the pharmacokinetic (PK) profile of HSK47977, delivering excellent oral bioavailability and superior systemic exposure after oral dosing. These advances translate into robust in‑vivo efficacy that is comparable with BMS‑986458 in CDX models. Oral administration of HSK47977 induces deep, sustained BCL6 degradation, resulting in pronounced tumor regression in CDX studies. Non‑clinical safety assessments demonstrate that HSK47977 is well tolerated in vivo following 28‑day toxicity studies in rats and dogs. Guided by mechanistic insight, we devised a combination strategy to amplify therapeutic potency. Because BCL6 acts as a transcriptional repressor, its degradation can up‑regulate the anti‑apoptotic protein BCL2, providing a rationale for concurrent BCL2 inhibition. Synergistic activity between HSK47977 and a BCL2 inhibitor was confirmed in both cell‑based assays and xenograft models; notably, low‑dose HSK47977 combined with a BCL2 inhibitor achieved robust tumor regression in CDX models. In summary, HSK47977 is a potent, orally deliverable BCL6 degrader distinguished by its novel CRBN ligand. Co‑administration with a BCL2 inhibitor markedly enhances antitumor efficacy, offering a promising therapeutic avenue for patients with DLBCL. HSK47977 has cleared IND in China and the USA, and a Phase I trial is ongoing, showing encouraging preliminary efficacyin heavily pre‑treated R/R FL patients, supporting continued development for NHL treatment.