CHEMICAL PROBE DISCOVERY
Small molecule chemical tools are valuable reagents for investigating the fundamental biological mechanisms of disease, and for target validation in drug discovery. We develop first-in-class selective chemical probes for novel targets in the neurodegeneration and neurooncology disease areas, and use them to interrogate cellular signalling pathways and validate new therapeutic targets.
- F. M. Ferguson*, B. Nabet*, et al. Discovery of a selective inhibitor of Doublecortin Like
- F. M. Ferguson*, Z. M. Doctor*, et al. Discovery of covalent CDK14 inhibitors with pan-TAIRE family specificity., Cell Chem. Biol. 2019, DOI: 10.1016/j.chembiol.2019.02.015.
TARGETED PROTEIN DEGRADATION
Targeted protein degradation (TPD) is an innovative chemical approach, whereby rather than inhibiting enzymatic function, proteins are selectively targeted for degradation by the proteasome. TPD is of interest in drug development as it can address previously inaccessible targets. Despite this, relatively little is understood about the factors governing a targets propensity for ubiquitination and degradation by specific E3-ligases, and the influence of chemical and cell type specific variables on the effects of a given degrader molecule. We tackle fundamental challenges in degrader design and discovery using chemoproteomic approaches, and develop chemical and chemical genetic degrader tools to answer mechanistic questions about target biology and the ubiquitin proteasome system.
- K. A. Donovan*, F. M. Ferguson*, et al. Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development. Cell, 2020, DOI: j.cell.2020.10.038.
- B. Nabet*, F. M. Ferguson*, et al. Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules. Nat. Comms, 2020, DOI: 10.1038/s41467-020-18377-w.
CHEMICAL CONTROL OF MISFOLDED PROTEIN FATE
The accumulation of misfolded proteins concurrent with disease progression is a hallmark of neurodegenerative disorders known collectively as proteinopathies. An important class of these is the tauopathies, such as Alzheimer’s disease (AD) and Frontotemporal dementia (FTD), which are linked to the misfolding of tau protein. However, how these aggregated species contribute to disease etiology and progression remains unclear. A key challenge in the field is the lack of tool compounds able to exert spatiotemporal control over misfolded protein levels that can be used to interrogate their function across multiple disease models. We harness TPD and related technologies to develop potent degraders for proteinopathies, and study their effects in patient derived models of disease.
- M. C. Silva*, F. M. Ferguson*, et al. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. eLife, 2019, DOI: 10.7554/eLife.45457.
In addition to the presence of misfolded proteins, neurodegenerative diseases are driven by misregulated protein postranslational modifications (PTMs), such as phosphorylation, acetylation, and methylation. The enzymes that write and erase these marks have multiple substrates, limiting the precision with which we can manipulate PTMs on a single protein of interest in living cells. We develop new tools (heterobifunctional dimerizers and molecular glues) allowing us to investigate the effects of PTMs on protein misfolding, accumulation and disease phenotypes.