Open AccessDiscovery of Potent Small-Molecule Inhibitors of MLL Methyltransferase
Author(s) -
Ting-Rong Chern,
Liu Liu,
E.M. Petrunak,
Jeanne A. Stuckey,
Mi Wang,
Denzil Bernard,
Haibin Zhou,
Shirley Lee,
Yali Dou,
Shaomeng Wang
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00229
Subject(s) - methyltransferase , small molecule , cocrystal , histone methyltransferase , fusion protein , methylation , leukemia , computational biology , drug discovery , cancer research , chemistry , lineage (genetic) , biology , gene , biochemistry , genetics , molecule , recombinant dna , hydrogen bond , organic chemistry
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 S -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.