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Discovery of Potent Small-Molecule Inhibitors of MLL Methyltransferase.

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 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.

SUBMITTER: Chern TR

PROVIDER: S-EPMC7294728 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Discovery of Potent Small-Molecule Inhibitors of MLL Methyltransferase.

Chern Ting-Rong TR Liu Liu L Petrunak Elyse E Stuckey Jeanne A JA Wang Mi M Bernard Denzil D Zhou Haibin H Lee Shirley S Dou Yali Y Wang Shaomeng S

ACS medicinal chemistry letters 20200514 6

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 <i>S</i>-adenosylmethionine-based focused chemical library which led to the discovery of potent small-molecule inhibitors directly targeting th ...[more]

PMID: 32551023

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