To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.

中文翻译：

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优化形状互补性有助于发现有效的三环 BCL6 抑制剂

为了鉴定对 B 细胞淋巴瘤 6 蛋白的 BTB 结构域具有增强结合亲和力的新化学系列，我们针对 Val18 附近的一个子口袋。由于没有机会进行强极性相互作用，我们专注于通过将环融合到我们的喹啉酮铅系列上来获得紧密的形状互补性。在探索了不同大小的环之后，我们确定了一个构象受限的核心，它可以最佳地填充可用空间，从而产生有效的 BCL6 抑制剂。通过 X 射线结构引导设计，结合高效的合成化学来制造新的核心结构，通过添加 7 个重原子，活性提高了 300 倍以上。