title: Identification of novel small-molecule inhibitors targeting menin-MLL interaction, repurposing the antidiarrheal loperamide.
abstract: Leukemia with a mixed lineage leukemia (MLL) rearrangement, which harbors a variety of MLL fusion proteins, has a poor prognosis despite the latest improved treatment options. Menin has been reported to be a required cofactor for the leukemogenic activity of MLL fusion proteins. Thus, the disruption of the protein-protein interactions between menin and MLL represents a very promising strategy for curing MLL leukemia. Making use of menin-MLL inhibitors with a shape-based scaffold hopping approach, we have discovered that the antidiarrheal loperamide displays previously unreported mild inhibition for the menin-MLL interaction (IC50 = 69 ± 3 μM). In an effort to repurpose this drug, a series of chemical modification analyses was performed, and three of the loperamide-based analogues, DC_YM21, DC_YM25 and DC_YM26 displayed better activities with IC50 values of 0.83 ± 0.13 μM, 0.69 ± 0.07 μM and 0.66 ± 0.05 μM, respectively. Further treatment with DC_YM21 demonstrated potent and selective blockage of proliferation and induction of both cell cycle arrest and differentiation of leukemia cells harboring MLL translocations, which confirmed the specific mechanism of action. In conclusion, molecules of a novel scaffold targeting menin-MLL interactions were reported and they may serve as new potential therapeutic agents for MLL leukemia.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. nxzhang@mail.shcnc.ac.cn.
authors.forename: Liyan
authors.initials: L
authors.lastname: Yue
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Du
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Chen
authors.forename: Lianchun
authors.initials: L
authors.lastname: Li
authors.forename: Fulin
authors.initials: F
authors.lastname: Lian
authors.forename: Bidong
authors.initials: B
authors.lastname: Zhang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Yuanchao
authors.initials: Y
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Zhou
authors.forename: Naixia
authors.initials: N
authors.lastname: Zhang
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Yang
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
mesh_terms: D000930:Antidiarrheals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008139:Loperamide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000930:Antidiarrheals; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; D051788:Myeloid-Lymphoid Leukemia Protein; D008139:Loperamide