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Tops $2 million, supports small molecule research to identify new approaches to modulating drug target

Brittany Jennings
March 26, 2021


Each day, Stephen Frye, Ph.D., works to identify pharmacologic approaches to intervene in novel drug targets within stephen_fryethe human body with the goal of creating new therapeutic interventions that will directly aid patients.

Today, he’s pushing his work further with the support of a prestigious Maximizing Investigators’ Research Award, a mechanism that aims to enhance investigator scientific productivity and the chances for important breakthroughs. The five-year grant totals $2,129,195 and will support his research project, “Probing Allostery In Methyl-Lysine Reader Domains.”

“This award will enable a broad, thematic approach to establishing allosteric interventions in an emerging class of drug targets, methyl-lysine reader domains,” said Frye, a Fred Eshelman Distinguished Professor and Co-Director of the Center for Integrative Chemical Biology and Drug Discovery.

Frye explained that his work will examine allosteric interactions (the ability of proteins or protein complexes to have their function modulated via multiple, interacting ligand binding sites) in chromatin regulatory complexes. This is a phenomenon that may point to unique opportunities for pharmacologic intervention – including the ability to increase a protein’s activity which is not possible with direct active-site inhibitors. Frye and his team will specifically target methyl-lysine (Kme) reader domains – a focus of epigenetic research due to their crucial role in gene regulation.

“The molecular details of chromatin regulation are just beginning to be understood and chemical biology is poised to play a central role in advancing scientific knowledge and assessing therapeutic opportunities in this field,” Frye said.

He added that the advantages of a small molecule driven approach to exploring chromatin biology such as this are numerous and include temporal resolution; mechanistic flexibility; ease of delivery in cells and potentially, in vivo; and an immediate transition to therapeutic discovery.

Additional collaborators on this project include: Lindsey James (Assistant Prof, CBMC, ESOP), Dmitri Kireev (Prof, CBMC, ESOP), Ken Pearce (Prof, CBMC, ESOP, Co-Director, CICBDD), Jacky Norris-Drouin (Research Associate, CICBDD), Postdoctoral fellow, Mélanie Uguen, and graduate student Devan Shell.

“Allosteric interactions in chromatin regulatory complexes are critically important phenomena that create unique opportunities for pharmacologic intervention. We will focus our future endeavors on this exciting frontier in the methyl-lysine reader family,” Frye added.

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