The overall goal of this program is to understand how epigenetic mechanisms of gene expression contribute to the development and progression of cancer in a cell-lineage specific fashion. As an initial effort, we have focused on the development of small molecules and chemical tools to profile and perturb the activity of lysine acetyltransferases (KATs). These enzymes catalyze lysine acetylation, a widespread protein posttranslational modification involved in the regulation of gene expression, DNA repair, protein stability, and metabolism. To better understand the role of protein acetylation in cancer, we have taken a multi-pronged approach. First, we have developed a method capable of globally profiling cellular KAT activities. This method is being applied to cell-based models to identify KATs whose differential activity regulates acetylation-mediated reprogramming of metabolism and gene expression observed in cancer. Second, we have developed a separation-based assay for the analysis of lysine acetyltransferase (KAT) enzymes. Currently we are working together with colleagues at the National Center for Advanced Translational Science (NCATS) to apply this assay to identify cell-active inhibitors of KATs known to collaborate with oncogenic transcription factors in leukemia. This assay will also be applied to understand the metabolic sensitivity of chromatin-modifying enzymes. These studies provide the basis for the application of similar approaches to diverse classes of epigenomic regulators, and support the discovery of novel biological mechanisms in cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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Shirakawa, Kotaro; Wang, Lan; Man, Na et al. (2016) Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. Elife 5:
Shrimp, Jonathan H; Sorum, Alexander W; Garlick, Julie M et al. (2016) Characterizing the Covalent Targets of a Small Molecule Inhibitor of the Lysine Acetyltransferase P300. ACS Med Chem Lett 7:151-5
Sorum, Alexander W; Shrimp, Jonathan H; Roberts, Allison M et al. (2016) Microfluidic Mobility Shift Profiling of Lysine Acetyltransferases Enables Screening and Mechanistic Analysis of Cellular Acetylation Inhibitors. ACS Chem Biol 11:734-41
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Zengeya, Thomas T; Kulkarni, Rhushikesh A; Meier, Jordan L (2015) Modular synthesis of cell-permeating 2-ketoglutarate esters. Org Lett 17:2326-9
Montgomery, David C; Sorum, Alexander W; Meier, Jordan L (2015) Defining the orphan functions of lysine acetyltransferases. ACS Chem Biol 10:85-94
Montgomery, David C; Sorum, Alexander W; Guasch, Laura et al. (2015) Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors. Chem Biol 22:1030-9
Montgomery, David C; Sorum, Alexander W; Meier, Jordan L (2014) Chemoproteomic profiling of lysine acetyltransferases highlights an expanded landscape of catalytic acetylation. J Am Chem Soc 136:8669-76
Kulkarni, Rhushikesh A; Meier, Jordan L (2014) Chemical cryptology of cancer's histone code. Chem Biol 21:1419-21
Kang, JeenJoo S; Meier, Jordan L; Dervan, Peter B (2014) Design of sequence-specific DNA binding molecules for DNA methyltransferase inhibition. J Am Chem Soc 136:3687-94