Discovery of Potent Small-Molecule Inhibitors of MLL Methyltransferase

Ting-Rong Chern; Liu Liu; Elyse Petrunak; Jeanne A Stuckey; Mi Wang; Denzil Bernard; Haibin Zhou; Shirley Lee; Yali Dou; Shaomeng Wang

doi:10.1021/acsmedchemlett.0c00229

Discovery of Potent Small-Molecule Inhibitors of MLL Methyltransferase

ACS Med Chem Lett. 2020 May 14;11(6):1348-1352. doi: 10.1021/acsmedchemlett.0c00229. eCollection 2020 Jun 11.

Authors

Affiliation

¹ Department of Medicinal Chemistry, Department of Internal Medicine, Department of Pharmacology, Department of Pathology, and Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.

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.