title: Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening.
abstract: Disrupting the interaction between mixed lineage leukemia (MLL) fusion protein and menin provides a therapeutic approach for MLL-mediated leukemia. Here, we aim to discover novel inhibitors targeting the menin-MLL interface with virtual screening. Both structure-based molecular docking and ligand-based pharmacophore models were established, and the models used for compound screening show a remarkable ability to retrieve known active ligands from decoy molecules. Verified by a fluorescence polarization assay, five hits with novel scaffolds were identified. Among them, DCZ_M123 exhibited potent inhibitory activity with an IC50 of 4.71 ± 0.12 μM and a KD of 14.70 ± 2.13 μM, and it can effectively inhibit the human MLL-rearranged leukemia cells MV4;11 and KOPN8 with GI50 values of 0.84 μM and 0.54 μM, respectively.
authors: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
authors: Yuan
authors: Y
authors: Xu
authors: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
authors: Liyan
authors: L
authors: Yue
authors: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
authors: Yulan
authors: Y
authors: Wang
authors: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
authors: Jing
authors: J
authors: Xing
authors: School of Life Science and Technology, Shanghai Tech University , Shanghai 200031, China.
authors: Zhifeng
authors: Z
authors: Chen
authors: Shanghai ChemPartner LifeScience Co., Ltd., #5 Building, 998 Halei Road, Shanghai 201203, China.
authors: Zhe
authors: Z
authors: Shi
authors: Shanghai ChemPartner LifeScience Co., Ltd., #5 Building, 998 Halei Road, Shanghai 201203, China.
authors: Rongfeng
authors: R
authors: Liu
authors: Shanghai ChemPartner LifeScience Co., Ltd., #5 Building, 998 Halei Road, Shanghai 201203, China.
authors: Yu-Chih
authors: YC
authors: Liu
authors: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
authors: Xiaomin
authors: X
authors: Luo
authors: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|School of Life Science and Technology, Shanghai Tech University , Shanghai 200031, China.
authors: Hualiang
authors: H
authors: Jiang
authors: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|School of Life Science and Technology, Shanghai Tech University , Shanghai 200031, China.
authors: Kaixian
authors: K
authors: Chen
authors: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
authors: Cheng
authors: C
authors: Luo
authors: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
authors: Mingyue
authors: M
authors: Zheng
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D000970:Antineoplastic Agents; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein