美国波士顿儿童医院Scott A. Armstrong团队合成出一个Menin-MLL的抑制剂，其能够在MLL重排白血病模型中诱导特异性染色质改变并根除疾病。2019年12月9日出版的《癌细胞》发表了这项成果。

基于结构的设计，研究人员产生了有效的、高选择性的、可口服生物利用的小分子抑制剂VTP50469。带有MLL重排的细胞系对VTP50469有选择性的反应。VTP50469使Menin脱离了蛋白质复合物，并抑制了某些基因上MLL的染色质占位。MLL结合的丧失导致基因表达、分化和凋亡的改变。使用VTP50469治疗时，患有MLL重排（MLL-r）急性髓细胞性白血病或MLL-r急性淋巴细胞性白血病（ALL）的患者异种移植（PDX）模型显示出白血病负担显著降低。 治疗后多只植入了MLL-r ALL的小鼠保持无病状态超过1年。这些数据表明，该方法可快速转化为临床试验。

据了解，抑制Menin（MEN1）和MLL（MLL1、KMT2A）相互作用是MLL-r白血病的潜在治疗策略。

附：英文原文

Title: A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia

Author: Andrei V. Krivtsov, Kathryn Evans, Jayant Y. Gadrey, Benjamin K. Eschle, Charlie Hatton, Hannah J. Uckelmann, Kenneth N. Ross, Florian Perner, Sarah N. Olsen, Tara Pritchard, Lisa McDermott, Connor D. Jones, Duohui Jing, Ali Braytee, Diego Chacon, Eric Earley, Brian M. McKeever, David Claremon, Andrew J. Gifford, Heather J. Lee, Beverly A. Teicher, John E. Pimanda, Dominik Beck, Jennifer A. Perry, Malcolm A. Smith, Gerard M. McGeehan, Richard B. Lock, Scott A. Armstrong

Issue&Volume: 2019/12/09

Abstract: Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.

DOI: 10.1016/j.ccell.2019.11.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30521-5