Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences, and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY, New York, USA.
Sci Adv. 2024 Aug 30;10(35):eado1432. doi: 10.1126/sciadv.ado1432. Epub 2024 Aug 28.
The histone acylation reader eleven-nineteen leukemia (ENL) plays a pivotal role in sustaining oncogenesis in acute leukemias, particularly in -rearranged (-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 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.
组蛋白酰化读取蛋白十一号十九白血病（ENL）在维持急性白血病中的致癌作用中起着关键作用，特别是在 - 重排（-r）白血病中。ENL 依赖其读取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。在这里，我们报告了 MS41 的开发，这是一种高度有效和选择性的 von Hippel-Lindau 募集的 ENL 降解剂，可有效抑制依赖 ENL 的白血病细胞的生长。MS41 诱导的 ENL 降解降低了与 ENL 相关的转录延伸机制在染色质上的占有率，从而抑制了关键的致癌基因表达程序，并激活了分化基因。MS41 在体内耐受性良好，并在白血病异种移植小鼠模型中显著抑制白血病进展。值得注意的是，MS41 还诱导了在威尔姆斯瘤中发现的突变 ENL 蛋白的降解。我们的研究结果强调了药理学 ENL 降解治疗依赖 ENL 的癌症的治疗潜力，使 MS41 不仅成为有价值的化学探针，而且也是进一步开发的潜在抗癌治疗药物。
