6U9N

MLL1 SET N3861I/Q3867L bound to inhibitor 14 (TC-5139)

Summary for 6U9N

• Entry DOI: 10.2210/pdb6u9n/pdb
• Related: 6U9K 6U9M
• Descriptor: Histone-lysine N-methyltransferase, 5'-{[(3S)-3-amino-3-carboxypropyl]({1-[(4-chlorophenyl)methyl]azetidin-3-yl}methyl)amino}-5'-deoxyadenosine, ZINC ION, ... (4 entities in total)
• Functional Keywords: transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 37739.27

Authors

Petrunak, E.M.,Stuckey, J.A. (deposition date: 2019-09-09, release date: 2020-07-01, Last modification date: 2023-10-11)

Primary citation

Chern, T.R.,Liu, L.,Petrunak, E.,Stuckey, J.A.,Wang, M.,Bernard, D.,Zhou, H.,Lee, S.,Dou, Y.,Wang, S.
Discovery of Potent Small-Molecule Inhibitors of MLL Methyltransferase.
Acs Med.Chem.Lett., 11:1348-1352, 2020

PubMed Abstract: The mixed-lineage leukemia (MLL) protein, also known as MLL1, is a lysine methyltransferase specifically responsible for methylation of histone 3 lysine 4. MLL has been pursued as an attractive therapeutic target for the treatment of acute leukemia carrying the MLL fusion gene or MLL leukemia. Herein, we report the design, synthesis, and evaluation of an -adenosylmethionine-based focused chemical library which led to the discovery of potent small-molecule inhibitors directly targeting the MLL SET domain. Determination of cocrystal structures for a number of these MLL inhibitors reveals that they adopt a unique binding mode that locks the MLL SET domain in an open, inactive conformation.

PubMed: 32551023
DOI: 10.1021/acsmedchemlett.0c00229

Experimental method

X-RAY DIFFRACTION (1.95 Å)