Open AccessDiscovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin–MLL Interaction with Strong In Vivo Antitumor Activity
Author(s) -
Shilin Xu,
Angelo Aguilar,
Liyue Huang,
Tianfeng Xu,
Ke Zheng,
Donna McEachern,
Sally Przybranowski,
Caroline Foster,
Kaitlin P. Zawacki,
Zhaomin Liu,
Krishnapriya Chinnaswamy,
Jeanne A. Stuckey,
Shaomeng Wang
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00547
Subject(s) - chemistry , covalent bond , leukemia , in vivo , cancer research , fusion protein , small molecule , biochemistry , recombinant dna , immunology , biology , genetics , gene , organic chemistry
Targeting the menin-MLL protein-protein interaction is a new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein the structure-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 ( 16 ) as a highly potent and efficacious covalent menin inhibitor. M-808 effectively inhibits leukemia cell growth at low nanomolar concentrations and is capable of achieving partial tumor regression in an MV4;11 xenograft tumor model in mice at a well-tolerated dose schedule. Determination of the co-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinity, covalent interactions. M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation toward developing a new therapy for the treatment of MLL leukemia.