Structure-guided DOT1L probe optimization by label-free ligand displacement Journal Article
| Authors: | Yi, J. S.; Federation, A. J.; Qi, J.; Dhe-Paganon, S.; Hadler, M.; Xu, X.; St Pierre, R.; Varca, A. C.; Wu, L.; Marineau, J. J.; Smith, W. B.; Souza, A.; Chory, E. J.; Armstrong, S. A.; Bradner, J. E. |
| Article Title: | Structure-guided DOT1L probe optimization by label-free ligand displacement |
| Abstract: | The DOT1L lysine methyltransferase has emerged as a validated therapeutic target in MLL-rearranged (MLLr) acute leukemias. Although S-adenosylmethionine competitive inhibitors have demonstrated pharmacological proof-of-principle in MLLr-leukemia, these compounds require further optimization to improve cellular potency and pharmacokinetic stability. Limiting DOT1L inhibitor discovery and ligand optimization have been complex biochemical methods often using radionucleotides and cellular methods requiring prolonged culture. We therefore developed a new suite of assay technologies that allows comparative assessment of chemical tools for DOT1L in a miniaturized format. Coupling these assays with structural information, we developed new insights into DOT1L ligand binding and identified several functionalized probes with increased cellular potency (IC50 values ∼10 nM) and excellent selectivity for DOT1L. Together these assay technologies define a platform capability for discovery and optimization of small-molecule DOT1L inhibitors. © 2014 American Chemical Society. |
| Keywords: | controlled study; protein expression; unclassified drug; dose response; nonhuman; cell proliferation; high throughput screening; acute leukemia; protein purification; molecular recognition; crystal structure; ligand binding; anisotropy; s adenosylmethionine; isothermal titration calorimetry; antileukemic agent; chemoluminescence; priority journal; article; ic50; dot1l inhibitor |
| Journal Title: | ACS Chemical Biology |
| Volume: | 10 |
| Issue: | 3 |
| ISSN: | 1554-8929 |
| Publisher: | American Chemical Society |
| Date Published: | 2015-03-20 |
| Start Page: | 667 |
| End Page: | 674 |
| Language: | English |
| DOI: | 10.1021/cb500796d |
| PROVIDER: | scopus |
| PUBMED: | 25397901 |
| PMCID: | PMC4504433 |
| DOI/URL: | |
| Notes: | Export Date: 4 May 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work