The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustained depletion of BCL6 in vivo. We observed a sharp degradation SAR, where subtle structural changes conveyed the ability to induce degradation of BCL6. CCT373566 showed modest in vivo efficacy in a lymphoma xenograft mouse model following oral dosing.

中文翻译：

---

改善的结合亲和力和药代动力学使 BCL6 在体内持续降解


转录抑制因子 BCL6 是一种致癌驱动因子，被发现在淋巴恶性肿瘤中失调。在此，我们报告了我们之前报道的苯并咪唑酮分子胶型降解剂CCT369260到CCT373566的优化，CCT373566 是一种适用于体内持续消耗 BCL6 的高效探针。我们观察到急剧的降解 SAR，其中细微的结构变化表达了诱导 BCL6 降解的能力。 CCT373566在口服给药后的淋巴瘤异种移植小鼠模型中显示出适度的体内疗效。