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October 4, 2010
Volume 88, Number 40
p. 8

Perturbing A Cancer Reader

Chemical Biology: Locking a protein that recognizes markers on chromatin shrinks tumors in mice

Carmen Drahl

Block On (+)-JQ1 (mostly yellow) interacts with a pocket on BRD4 (mostly pink) through a hydrogen bond (dotted line). Panagis Filippakopoulos
Block On (+)-JQ1 (mostly yellow) interacts with a pocket on BRD4 (mostly pink) through a hydrogen bond (dotted line).
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By targeting a specific protein pocket, researchers have found a way to block a protein motif that reads chemical marks on genetic material that regulates the transcription of genes. The strategy could lead to new treatments for cancer and other diseases.

Until recently, scientists have focused on regulating proteins that add or remove so-called epigenetic marks, such as histone deacetylase enzymes. Now, chemical biologists Jun Qi and James E. Bradner of Dana-Farber Cancer Institute and Harvard Medical School, structural biologist Stefan Knapp of Oxford University and the Structural Genomics Consortium, and colleagues have found a way to block the activity of a protein module called BRD4, which neither adds nor removes but instead “reads” lysine acetylation marks on genetic material (Nature, DOI: 10.1038/nature09504).

(+)-JQ1

They discovered (+)-JQ1, a molecule that nestles in a largely hydrophobic pocket on BRD4, preventing the protein-protein interaction between BRD4 and acetylated histone proteins in chromatin. Giving (+)-JQ1 to mice with an aggressive and rare form of cancer in which BRD4 becomes part of an abnormal, fused protein led to tumor death.

“We consider JQ1 a tool compound,” Knapp says. “It allows us to study how these readers participate in the development of disease.” Dana-Farber has filed for patents on (+)-JQ1 derivatives that might inspire drugs to treat diseases.

Efforts “like this ultimately lay the foundation for clinical studies, and I think this work is an important step toward that,” says Philip A. Cole, who studies gene regulation at Johns Hopkins University School of Medicine.

GlaxoSmithKline researchers led by Kevin Lee presented a similar strategy for blocking epigenetic readers in August at the ACS national meeting in Boston. “This paper shows the promise and potential of inhibition of the reader domains within epigenetics,” Lee says.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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