J Med Chem. 2023 Apr 27;66(8):5892-5906. doi: 10.1021/acs.jmedchem.3c00155. Epub 2023 Apr 7.
B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and exposure of the non-degrading isomer, , of our recently published degrader, . The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of , a potent inhibitor of BCL6 with a good profile. Modest efficacy was achieved in a lymphoma xenograft mouse model after oral dosing.
B 细胞淋巴瘤 6（BCL6）是弥漫性大 B 细胞淋巴瘤（DLBCL）的转录抑制剂和致癌驱动因子。在这里，我们报告了我们之前报道的三环喹啉酮系列对 BCL6 抑制作用的优化。我们试图提高我们最近发表的降解物的非降解异构体的细胞效力和暴露度，。我们抑制剂的主要限制是它们的高拓扑极性表面积（TPSA），导致外排率增加。降低分子量使我们能够在不显着降低溶解度的情况下去除极性和减少 TPSA。通过药代动力学研究指导的这些性质的仔细优化导致了发现，这是一种有效的 BCL6 抑制剂，具有良好的药代动力学特性。口服给药后，在淋巴瘤异种移植小鼠模型中观察到适度的疗效。
