Abstract:
:Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound 42 (M-89). M-89 binds to menin with a Kd value of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations. M-89 inhibits cell growth in the MV4;11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC50 values of 25 and 55 nM, respectively, and demonstrates >100-fold selectivity over the HL-60 leukemia cell line lacking MLL fusion. The determination of a co-crystal structure of M-89 in a complex with menin provides the structural basis for their high-affinity interaction. Further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Aguilar A,Zheng K,Xu T,Xu S,Huang L,Fernandez-Salas E,Liu L,Bernard D,Harvey KP,Foster C,McEachern D,Stuckey J,Chinnaswamy K,Delproposto J,Kampf JW,Wang Sdoi
10.1021/acs.jmedchem.9b00021subject
Has Abstractpub_date
2019-07-11 00:00:00pages
6015-6034issue
13eissn
0022-2623issn
1520-4804journal_volume
62pub_type
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