Our Research Teams and Our Director
The Center will be an innovative and sustainable scientific force in the creation of chemical probes, drug candidates, assay technologies, and computational approaches to advance understanding of biological mechanisms and place UNC at the forefront of translational medicine.
Director, Center for Integrated Chemical Biology and Drug Discovery
ACCEPTING DOCTORAL STUDENTS
Ken Pearce is a Professor and Director of the Center of Chemical Biology and Drug Discovery at the University of North Carolina at Chapel Hill. Pearce is also the Director of the Lead Discovery and Characterization group. His primary interest and expertise is the application of various methods for conducting early drug and chemical probe discovery research. These techniques include the development of biochemical and cell assays, high-throughput screening, DNA-encoded library technology, peptide phage display, and mechanistic/biophysical studies. Projects are typically collaborative efforts with labs across the UNC campus and span numerous therapeutic areas, with a particular focus on oncology. He is motivated by collaborative team-based and therapeutically-aligned science, training the next generation of discovery scientists, and contributing to service opportunities at UNC.
Director, Applied Epigenetic Screening Technologies
ACCEPTING DOCTORAL STUDENTSLab Members
The Pattenden Lab develops innovative techniques in chromatin-based therapeutic target discovery and cancer diagnostics. Our research program enables discovery of novel molecular targets, pathways and mechanisms. Some of our current projects include:
Development of a cavitation enhancement technology to access archived tissues for epigenetics-based biomedical research
Collaborators: Dr. Ian Davis (Genetics, Pediatric Hematology/Oncology) and Dr. Paul Dayton (Biomedical Engineering)
Innovative new technologies that enable experimentally robust interrogation of epigenetic mechanisms are needed to broaden our understanding of epigenetic regulatory pathways in human development, disease, and therapeutic resistance. Formalin fixed, paraffin embedded (FFPE) tissues contain a wealth of information on human disease, however, extraction of high-quality chromatin (DNA together with associated nuclear proteins) from these samples for use in epigenetic assays has proven virtually impossible. We are exploring the use of a unique cavitation enhancement reagent in simplifying and standardizing chromatin extraction from FFPE tissues, with the goal of making archived biospecimens available for a broad range of epigenetic-based biomedical research.
Development of a First-in-Class High Throughput Assay Based on Chromatin Accessibility
Collaborators: Dr. Ian Davis (Genetics, Pediatric Hematology/Oncology
As appreciation of the importance of chromatin dysregulation in cancers has grown, chromatin regulatory proteins have emerged as promising targets for therapeutic discovery. Unlike alterations to the underlying DNA sequence, changes in chromatin states are both dynamic and reversible. Chromatin-related proteins are challenging targets for small molecule discovery since they frequently associate with multiple complexes with divergent cellular functions. For this reason, hit compounds derived from in vitro screening approaches based on a single chromatin-associated protein domain will likely suffer from significant off-target effects when tested in cells or in vivo.
To address the immediate need for cell-based chromatin screens, we have developed a target agnostic small molecule screening technology that exploits tumor-specific chromatin accessibility states as a relevant and direct functional readout. By targeting chromatin accessibility instead of a single transcription factor or chromatin regulatory protein, the limitations associated with in vitro screening and single protein target identification can be overcome. This screening technique represents a promising new paradigm in oncology drug discovery that will increase our mechanistic knowledge of tumor-specific changes in the epigenome and expand the repertoire of druggable targets.
Collaborators: Dr. Michael Jarster (Chemical Biology and Medicinal Chemistry
Cancerous cells develop a number of mechanisms to evade the checks and balances present in normal cells. One of the mechanisms by which tumor cells become immortal is by maintaining the length of the caps at the ends of chromosomes called telomeres. Telomere length is maintained by telomerase in ~85% of cancers and by the alternative lengthening of telomeres (ALT) pathway in the remaining ~15% of cancers. The ALT pathway is associated with poor prognosis, but the mechanisms by which ALT is induced are not well understood. ALT cells are frequently associated with the formation of extrachromosomal C-circles, which can be used as a readout for ALT activity. We are developing a high throughput assay using targeted small molecule chemical libraries to discover inhibitors of the ALT C-circle phenotype. Hit compounds will inform the key protein players in ALT maintenance and possibly reveal new therapeutic targets for ALT positive cancers.
Director, Chemical Biology
ACCEPTING DOCTORAL STUDENTSLab Members
The goal of the James lab is to undertake and lead innovative and novel projects focused on the chemical biology of chromatin regulation, with an emphasis on the development of small molecule chemical probes. Providing such tool compounds to the scientific community has the potential to open new avenues of research in various disease relevant fields and translate to compounds of therapeutic value. Specifically, we are focused on developing compounds to study the domains that recognize the post-translational modification, methylated lysine. Aberrant methylation levels and ensuing changes in gene expression patterns resulting from the altered expression of methyl-lysine (Kme) regulatory proteins is one mechanism by which such epigenetic factors contribute to disease. Kme reader domains have emerged as less precedented epigenetic targets, yet considering the abundant links to cancer genetics, they are well suited to become the next impactful target class of chromatin regulators for intervention.
Our work in this area has pioneered the biochemical assays and medicinal chemistry strategies for high-quality probe development for the methyl-lysine reader target class, as well as the means by which to evaluate probe selectivity, mechanism of action, and cellular activity. Using a variety of approaches, we utilize such chemical tools to improve our understanding of their molecular targets and the broader biological consequences of modulating these targets in disease, particularly cancer. We also think about developing novel methods and screening platforms to discover hit compounds to accelerate Kme reader probe discovery such as affinity-based combinatorial strategies, as well as novel ligand-based tools (see below) such as protein degradation reagents, or PROTACs, as potential therapeutic modalities. We have successfully developed numerous first-in-class chemical probes and currently have compounds in preclinical development (for example, see https://pharmacy.unc.edu/2019/12/pinnacle-hill-announces-first-project-agreement/).
Additionally, we collaborate closely with UNC faculty from various disciplines to provide medicinal chemistry and chemical biology expertise to bear on biological targets of therapeutic relevance.
Dr, James is committed to providing an inclusive, safe, and supportive research environment for trainees, teaching trainees to conduct rigorous, ethically sound, and responsible scientific research, and fulfilling the needs of trainees so that they can transition to the next phase of their careers.
Director, Lead Discovery and Characterization
ACCEPTING DOCTORAL STUDENTSLab Members
Currently, within the CICBDD Lead Discovery and Characterization Team, we develop comprehensive early drug discovery programs using a variety of methods including protein expression and purification, biochemical and cell assays, and screening in partnership with numerous collaborators at UNC. We have the ability to conduct compound screening using a library of over 200,000 drug-like small molecules assembled within the center. Our expertise is also in hit validation and triage methods, including the use of biophysical methods. Following successful hit discovery and validation, we work with collaborators and chemists within the center to produce structure-activity data and additional mode-of-action studies. Our ultimate goals are to: 1) produce high-quality chemical probes for exploring biology or drug targets, and 2) discover drug candidate molecules for the treatment of unmet medical needs.
The majority of our activities and interests are exploring targets within the epigenetic and chromatin modification network and prosecuting novel targets, including signal transduction proteins, enzymes, and protein-protein interactions, for the discovery of new potential cancer treatments. These techniques include the development of biochemical and cell assays, high-throughput screening, DNA-encoded library technology, peptide phage display, and mechanistic/biophysical studies. Targets for these discovery campaigns include proteins involved in epigenetic regulation, signal transduction, and enzymatic modifications.
Director, Medicinal ChemistryLab Members
The Wang lab is interested in developing drug leads/candidates for kinase, phosphate kinase and protein targets identified by UNC faculty and external investigators. We have successfully used the structure- and/or ligand-based drug design approaches to deliver compounds to clinic (MerTK inhibitors such as MRX-2843) or licensing (IDH1 inhibitor, co-developed with NCATs). We will continue to apply similar approaches for drug discovery towards new targets.
Our medicinal chemistry efforts are project-based with a faculty generated lead compound. We can support 3-5 hit to probe/lead projects concurrently. The typical timeline from completion of a screen to completion of leads is 1-2 years. Projects are prioritized primarily based on the quality of hits and project funding. To date, our most successful project has been the development of inhibitors of Mer kinase for the treatment of leukemia and immunosuppressive tumors, which has delivered a candidate MRX-2843 in clinical trials. A significant portion of this work was funded through a research contract as a member of NCI’s Chemical Biology Consortium (CBC). In addition, we were funded through the CBC to conduct structure activity relationship (SAR) studies to support lead development of inhibitors of IDH1 to treat glioblastoma. We have contributed to numerous drug discovery efforts with UNC faculty and external investigators. Most recently, we have been funded by NIH to develop probes for new targets to treat Alzheimer’s disease and MerTK/Axl dual and Tyro3 selective inhibitors for the treatment of cancer by targeting tumor cells and activating anti-tumor immunity.