Discovery of Potent Small-Molecule Inhibitors of MLL Methyltransferase
ACS MEDICINAL CHEMISTRY LETTERS
Authors: Chern, Ting-Rong; Liu, Liu; Petrunak, Elyse; Stuckey, Jeanne A.; Wang, Mi; Bernard, Denzil; Zhou, Haibin; Lee, Shirley; Dou, Yali; Wang, Shaomeng
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.
Chromatin Complexes Maintain Self-Renewal of Myeloid Progenitors in AML: Opportunities for Therapeutic Intervention
STEM CELL REPORTS
Authors: Uckelmann, Hannah J.; Armstrong, Scott A.
Abstract
Specific subgroups of acute myeloid leukemia (AML), including those containing MLL rearrangements and NPM1c mutations, possess characteristic stem cell-like gene expression profiles. These expression programs are highly dependent on components of the MLL histone methyltransferase complex, including Menin and DOT1L. Understanding the chromatin-based mechanisms through which cancer cells subvert certain aspects of normal stem cell biology helped identify specific vulnerabilities and trans- late them into targeted therapy approaches. Exciting progress has been made in the development of small-molecule inhibitors target-ing this epigenetic machinery in leukemia cells and prompted the development of clinical trials in patients with hematologic malig-nancies.
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