一种新型的DOT1L抑制剂EPZ-5676的作用机制及其研究进展

Mechanism of A New DOT1L Inhibitor EPZ-5676 and Its Research Progress

MLL基因重排阳性的急性白血病(MLL-r AL)恶性程度高,预后差。最新研究发现,MLL基因重排促进白血病发生发展的作用与DOT1L(DOT1-like)的蛋白有关。一种新型小分子抑制剂EPZ-5676具有抑制DOT1L的作用。细胞实验研究发现,EPZ-5676具有抑制增殖、促凋亡以及促分化的作用。EPZ-5676与多种抗白血病药物具有联合作用关系。荷瘤鼠实验也证实了该药可以抑制肿瘤生长。该药正在进行Ⅰ期临床试验,目前取得的结果提示该药非常有前景。本文综述了EPZ-5676的相关研究进展。

Leukemia carring translocation at the 11q23 locus is referred to MLL-rearranged（MLL-r） leukemia,and the occurrence of this genetic lesion is associated with a poor prognosis.The most common translocation chromosomes are chromosomes 4,9 and 10.Recently MLL protein was found to interact with DOTIL（DOT1-like） protein,which can promote leukemogenesis.A new DOTIL inhibitor EPZ-5676 can selectively inhibit proliferation,promote apoptosis and differentiation,which was also found to act synergistically with anti-AML（acute myeloid leukemia） and anti-ALL（acute lymphoblastic leukemia） drugs.EPZ-5676 can also induce sustained regression in a rat xenograft model of MLLrearranged leukemia.Now the novel drug is in phase I of clinical trail.The results suggest that the EPZ-5676 is promising.In this article,the mechanism of EPZ-5676 and its research progress are reviwed.