Targeting the menin-MLL1 complex for new therapeutics

在5%的成人急性髓系白血病(AML)中，染色体重排 发生混合系白血病基因(MLL，又称MLL1，以区别于ML2-4)， 这将导致MLL融合蛋白的表达。携带MLL的白血病患者 易位(以下也称为MLL白血病)预后非常差，只有35% 在目前的治疗下有5年的存活期，突出了开发新的和 MLL白血病更有效的治疗方法。 最常见的MLL重排是平衡的MLL易位，其中只有 一个MLL等位基因被截断并与70多个融合伙伴中的一个融合。大约1400人 来自MLL N末端的氨基酸保留在所有MLL融合蛋白中，并相互作用 直接与致癌的辅因子薄荷素有关。脑膜素-MLL蛋白-蛋白质相互作用是 Hox和Meis1基因的表达对MLL白血病的发生至关重要。 因此，利用小分子靶向研究脑膜素-MLL蛋白-蛋白质相互作用 抑制剂被认为是一种有前景的、分子靶向的治疗策略 髓系白血病的治疗。 尽管针对Menin-MLL蛋白的非肽小分子抑制剂的设计- 蛋白质相互作用是近年来人们积极追求的最好的小分子抑制剂。 目前只有优秀的实验室研究“工具”化合物可用于临床前研究。 学习。治疗MLL白血病的小分子薄荷素抑制剂研究进展 目前仍处于研究的早期阶段，还没有化合物进入人体临床试验。在……里面 这个R01奖项，我们建议设计和开发高度有效的，特定的，口服生物利用度， 非肽小分子抑制剂对脑膜素-MLL蛋白-蛋白质相互作用的影响 携带MLL融合的AML的治疗。

In 5% of adult human acute myeloid leukemia (AML), chromosomal rearrangements of the mixed lineage leukemia gene (MLL, also called MLL1 to distinguish it from MLL2-4) occur, which results in expression of MLL fusion proteins. Patients with leukemia carrying a MLL translocation (hereafter also called MLL leukemia) have very poor prognosis and only 35% have a 5-year survival with current treatments, highlighting the urgent need to develop new and more effective therapeutic approaches for MLL leukemia. The most common MLL rearrangements are balanced MLL translocations, in which only one MLL allele is truncated and fused with one of over 70 fusion partners. Approximately 1400 amino acids from the MLL N-terminus are retained in all the MLL fusion proteins, and interact directly with the oncogenic cofactor menin. The menin-MLL protein-protein interaction is essential for expression of HOX and MEIS1 genes to drive leukemogenesis in MLL leukemia. Consequently, targeting the menin-MLL protein-protein interaction using small-molecule inhibitors is considered to be a promising, molecularly targeted therapeutic strategy for the treatment of MLL leukemia. Although design of non-peptide small–molecule inhibitors targeting the menin-MLL protein- protein interaction has been actively pursued in recent years, the best small-molecule inhibitors currently available are only excellent laboratory research “tool” compounds for preclinical studies. Development of small-molecule menin inhibitors for the treatment of MLL leukemia is still in an early stage of research and no compound has progressed into human clinical trials. In this R01 award, we propose to design and develop highly potent, specific, orally bioavailable, non-peptide small-molecule inhibitors of the menin-MLL protein-protein interaction for the treatment of AML carrying MLL fusion.