Lindsey Ingerman James, Ph.D.
Assistant Professor, Division of Chemical Biology and Medicinal Chemistry
Director, Chemical Biology, the Center for Integrative Chemical Biology and Drug Discovery
3202 Marsico Hall, 125 Mason Farm Road, CB# 7363, Chapel Hill, NC, 27599
ACCEPTING DOCTORAL STUDENTS
Our goal is to undertake innovative and novel projects focused on the chemical biology of chromatin regulation, with an emphasis on the development of small molecule antagonists and chemical probes for the domains that recognize the post-translational modification, methylated lysine. The modification of lysine residues by methylation has a central role in chromatin function, primarily through the creation of binding sites for proteins that recognize these marks. 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. Methyl-lysine readers have emerged as less precedented epigenetic targets, yet considering prior successes with acetyl-lysine reader antagonists and the abundant links between cancer genetics and Kme reader domains, they are well suited to become the next impactful target class of chromatin regulators for intervention via chemical probes.
We are interested in modulating the activity of chromatin reader proteins with small-molecule ligands, specifically potent and selective chemical probes, in order to open new avenues of research in the field of chromatin biology and potentially translate to compounds of therapeutic value. Our work in this area has pioneered the biochemical assays and medicinal chemistry strategies for high quality probe development for this untapped 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 cells. We are also 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 innovative techniques utilizing our developed antagonists to more fully understand the dynamic nature of chromatin regulation. Additionally, we have a specific interest in the application of antagonists for Kme reader domains, as well as other classes of epigenetic regulators, toward the study of HIV latency, as strategies that promote viral reactivation by disrupting repressive epigenetic processes represent a promising step toward a cure for HIV.
- Discovery of a 53BP1 small molecule antagonit using a focused DNA-encoded library screen
- Development of VHL-recruiting STING PROTACs that suppress innate immunity
- Discovery of a potent and selective targeted NSD2 degrader for reduction of H3K36me2
- PROTAC linkerology leads to an optimized bivalent chemical degrader of Polycomb Repressive Complex 2 (PRC2) components
- Bioorthogonal chemical epigenetic modifiers enable dose-dependent CRISPR targeted gene activation
- Cdyl deficiency brakes neuronal excitability and nociception through promoting Kcnb1 transcription in peripheral sensory neurons
- A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization
- A peptidomimetic ligand targeting the chromodomain of MPP8 reveals HRP2’s association with the HUSH complex
- Discovery of an H3K36me3-derived peptidomimetic ligand with enhanced affinity for plant homeodomain finger protein 1 (PHF1)
- Improved methods for targeting epigenetic reader domains of acetylated and methylated lysine
- Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2
- Structural Basis for the Binding Selectivity of Human CDY Chromodomains.
- Evaluation of EED Inhibitors as a Class of PRC2-Targeted Small Molecules for HIV Latency Reversal. (ACS Editors’ Choice article)
- Assessing the Cell Permeability of Bivalent Chemical Degraders Using the Chloroalkane Penetration Assay.
- Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader.
- Getting a handle on chemical probes of chromatin readers.
- Targeting Regorafenib-Induced Toxicity through Inhibition of Gut Microbial β-Glucuronidases.
- TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss.
- Discovery and Characterization of a Cellular Potent Positive Allosteric Modulator of the Polycomb Repressive Complex 1 Chromodomain, CBX7.
- A General TR-FRET Assay Platform for High-Throughput Screening and Characterizing Inhibitors of Methyl-Lysine Reader Proteins.
- Canonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing.
- Discovery of selective activators of PRC2 mutant EED-I363M.
- POLYCOMB REPRESSIVE COMPLEXES AS KEY REGULATORS OF HIV LATENCY AND TARGETS FOR LATENCY REVERSAL
- DISCOVERY OF FIRST-IN-CLASS NSD2 DEGRADERS FOR CANCER THERAPY