6E1A

Menin bound to M-89

Summary for 6E1A

• Entry DOI: 10.2210/pdb6e1a/pdb
• Descriptor: Menin, (1S,2R)-2-[(4S)-2-methyl-4-{1-[(1-{4-[(pyridin-4-yl)sulfonyl]phenyl}azetidin-3-yl)methyl]piperidin-4-yl}-1,2,3,4-tetrahydroisoquinolin-4-yl]cyclopentyl methylcarbamate, praseodymium triacetate, ... (4 entities in total)
• Functional Keywords: inhibitor, protein binding, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 63309.30

Authors

Stuckey, J.A. (deposition date: 2018-07-09, release date: 2019-07-10, Last modification date: 2023-10-11)

Primary citation

Aguilar, A.,Zheng, K.,Xu, T.,Xu, S.,Huang, L.,Fernandez-Salas, E.,Liu, L.,Bernard, D.,Harvey, K.P.,Foster, C.,McEachern, D.,Stuckey, J.,Chinnaswamy, K.,Delproposto, J.,Kampf, J.W.,Wang, S.
Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein-Protein Interaction.
J.Med.Chem., 62:6015-6034, 2019

PubMed 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 (M-89). M-89 binds to menin with a 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 IC 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.

PubMed: 31244110
DOI: 10.1021/acs.jmedchem.9b00021

Experimental method

X-RAY DIFFRACTION (3.1 Å)