Chemical control of chromatin signaling in cancer
2019年5月27日 15:00 - 16:00

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Yokohama MainOfficeBldg.Hall

Dr. Michael A. Erb

Department of Chemistry, Scripps Research

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Pathogenic transcriptional regulatory networks sustain malignant
cell phenotypes in human cancers. We have previously identified
that the transcriptional co-activator, ENL, is essential for the
survival of diverse acute leukemia in both cellular and animal
models of the disease but is dispensable for the survival of
hematopoietic stem and progenitor cells. Thus, we predict that
ENL-targeted anti-cancer agents will possess favorable therapeutic
windows and have therefore endeavored to discover small-molecule
inhibitors of ENL. The ENL YEATS domain recognizes acylated lysine
residues within amino-terminal histone tails and this function
is essential for both the localization of ENL to chromatin and
for its ability to sustain leukemic proliferation.

We developed an ultra-high-throughput screening (uHTS) assay that
reports on the association of a synthetic histone peptide to
recombinant ENL YEATS domain and screened a collection of 250,000
small molecules. Validated hits were identified among false
positives using a novel target engagement assay, resulting in the
classification of two structurally distinct chemical scaffolds
as ENL YEATS inhibitors. Hits were optimized via hit expansion
studies and iterative medicinal chemistry to yield selective
ENL YEATS inhibitors. These data will support the development
of ENL YEATS antagonists as in vivo chemical probes and
targeted anti-cancer agents.

Takashi Umehara