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A leading academic center focused on translating UNC biomedical science into the discovery of small molecule medicines and chemical research tools.

The Center has focused on cancer relevant drug discovery and chemical biology research and seeks to expand into new collaborative areas identified as important for the campus, including neuroscience and infectious diseases.

Current Collaborations

The Center’s mission is to bring dedicated medicinal chemistry expertise to bear on biological targets of therapeutic relevance under investigation by UNC faculty. Synthetic chemists, assay development and compound profiling scientists work in the Center

Graduate student in the lab at Center for Integrative Chemical Biology and Drug Discovery

and create dedicated, multidisciplinary project teams with other groups on campus to progress targets through the drug discovery and early development process.

The first targeted therapeutic from the Center designed to reactivate the innate immune response in cancer and block survival signaling pathways in many solid and hematologic malignancies is advancing through clinical trials. In addition to collaborative drug discovery projects, the Center has a basic science focus in the area of chromatin regulation. The Center’s chromatin science is centered on methyl-lysine as a posttranslational modification and the protein-protein interactions that it facilitates. The first chemical probes for methyl-lysine reader proteins were discovered in the CICBDD and are being used to validate novel interventions in cancer and other diseases.

 

An innovative and sustainable scientific force for the creation of new small molecule therapeutics to improve public health and transform the drug discovery paradigm

Graphic depicting what we do and how we get there

Reprinted From

Dr. Lindsey James
Lindsey James, PhD, Assistant Professor
Director, Chemical Biology

. 2021 Nov 15.

doi: 10.1038/s41589-021-00898-0. Online ahead of print.

A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization

Affiliations

Abstract

Nuclear receptor-binding SET domain-containing 2 (NSD2) is the primary enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36), a mark associated with active gene transcription and intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two proline-tryptophan-tryptophan-proline (PWWP) domains and five plant homeodomains (PHDs) believed to serve as chromatin reading modules. Here, we report a chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1, antagonizes PWWP1 interaction with nucleosomal H3K36me2 and selectively engages endogenous NSD2 in cells. UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 that result from translocations prevalent in multiple myeloma (MM). Mutations of other NSD2 chromatin reader domains also increase NSD2 nucleolar localization and enhance the effect of UNC6934. This chemical probe and the accompanying negative control UNC7145 will be useful tools in defining NSD2 biology.

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