一种有效且选择性的 ENL 降解剂可抑制致癌基因表达和白血病进展。
A potent and selective ENL degrader suppresses oncogenic gene expression and leukemia progression.
发表日期：2024 Aug 30
作者：
Zhaoyu Xue, Lihuai Qin, Hongwen Xuan, Kaixiu Luo, Mengying Huang, Ling Xie, Yangzhou Su, Longxia Xu, Josiah Harsh, Brandon Dale, Xiaobing Shi, Xian Chen, H Ümit Kaniskan, Jian Jin, Hong Wen
来源：
Epigenetics & Chromatin
摘要：
组蛋白酰化阅读器 11-19 白血病 (ENL) 在维持急性白血病的肿瘤发生中发挥着关键作用，特别是在混合谱系白血病重排 (MLL-r) 白血病中。 ENL 依靠其阅读器域来识别促进致癌基因表达和白血病进展的组蛋白赖氨酸酰化。在此，我们报告了 MS41 的开发，这是一种高效、选择性的 von Hippel-Lindau 招募 ENL 降解剂，可有效抑制 ENL 依赖性白血病细胞的生长。 MS41 诱导的 ENL 降解减少了 ENL 相关转录延伸机制的染色质占用，从而抑制关键致癌基因表达程序并激活分化基因。 MS41 在体内具有良好的耐受性，并且在 MLL-r 白血病异种移植小鼠模型中显着抑制白血病进展。值得注意的是，MS41 还诱导肾母细胞瘤中发现的突变 ENL 蛋白的降解。我们的研究结果强调了药理 ENL 降解在治疗 ENL 依赖性癌症方面的治疗潜力，使 MS41 不仅是一种有价值的化学探针，而且是有待进一步开发的潜在抗癌疗法。
The histone acylation reader eleven-nineteen leukemia (ENL) plays a pivotal role in sustaining oncogenesis in acute leukemias, particularly in mixed-lineage leukemia-rearranged (MLL-r) leukemia. ENL relies on its reader domain to recognize histone lysine acylation promoting oncogenic gene expression and leukemia progression. Here, we report the development of MS41, a highly potent and selective von Hippel-Lindau-recruiting ENL degrader that effectively inhibits the growth of ENL-dependent leukemia cells. MS41-induced ENL degradation reduces the chromatin occupancy of ENL-associated transcription elongation machinery, resulting in the suppression of key oncogenic gene expression programs and the activation of differentiation genes. MS41 is well-tolerated in vivo and substantially suppresses leukemia progression in a xenograft mouse model of MLL-r leukemia. Notably, MS41 also induces the degradation of mutant ENL proteins identified in Wilms' tumors. Our findings emphasize the therapeutic potential of pharmacological ENL degradation for treating ENL-dependent cancers, making MS41 not only a valuable chemical probe but also potential anticancer therapeutic for further development.