6WNH

Menin bound to inhibitor M-808

Summary for 6WNH

• Entry DOI: 10.2210/pdb6wnh/pdb
• Descriptor: Menin, methyl [(1S,2R)-2-{(1S)-2-(azetidin-1-yl)-1-(3-fluorophenyl)-1-[1-({1-[4-({1-[4-(piperidin-1-yl)butanoyl]azetidin-3-yl}sulfonyl)phenyl]azetidin-3-yl}methyl)piperidin-4-yl]ethyl}cyclopentyl]carbamate, 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: 63472.53

Authors

Stuckey, J.A. (deposition date: 2020-04-22, release date: 2020-05-13, Last modification date: 2023-10-18)

Primary citation

Xu, S.,Aguilar, A.,Huang, L.,Xu, T.,Zheng, K.,McEachern, D.,Przybranowski, S.,Foster, C.,Zawacki, K.,Liu, Z.,Chinnaswamy, K.,Stuckey, J.,Wang, S.
Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with StrongIn VivoAntitumor Activity.
J.Med.Chem., 63:4997-5010, 2020

PubMed Abstract: 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 () 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.

PubMed: 32338903
DOI: 10.1021/acs.jmedchem.0c00547

Experimental method

X-RAY DIFFRACTION (2.1 Å)