Cheryl H Arrowsmith | UHN Research

Cheryl Arrowsmith is a Senior Scientist at the Princess Margaret Cancer Centre, Professor in the Department of Medical Biophysics, University of Toronto, and the Chief Scientist of the Structural Genomics Consortium (SGC) at the University of Toronto. Her research focuses on the structural and chemical biology of chromatin and epigenetic regulatory factors especially as relates to cancer and drug discovery. In partnership with major pharmaceutical companies, she leads the SGC’s international open science program that is developing and distributing unencumbered Chemical Probes that support the discovery of new medicines. She received her Ph.D. from the University of Toronto and carried out postdoctoral research at Stanford University, and was co-founder of Affinium Pharmaceuticals, which developed a new medicine for multidrug resistant bacteria. She has published over 300 research articles, and was recognized by Clarivate Analytics as being among the worlds top 1% of highly cited scientists in 2018, 2019, 2021, 2022. She was elected an AAAS Fellow (2015), and a Fellow of the Royal Society of Canada (2020).

Epigenetics and Drug Discovery
Epigenetics refers to heritable differences in phenotype that are due to mechanisms other than differences in DNA sequence. Epigenetics involves a dynamic interplay between DNA methylation, posttranslational modification of histones and other proteins, and noncoding RNA networks that control gene expression programs in normal and diseased cells.
Mutations in chromatin regulatory genes and alterations of the cellular epigenome are prevalent in most cancers. Post-translational modifications (PTMs) on histone proteins serve as docking sites for chromatin-associated proteins, which in turn dictate dynamic conversion between transcriptionally active or silent chromatin states. The combinatorial nature of these modifications establishes a "histone code" which serves to expand the information present in the DNA-sequence of the genetic code. Lysine methylation is the most complex mark, and it plays a pivotal role in heterochromatin formation, transcriptional regulation and X-chromosome inactivation. Mutations or aberrant expression of proteins containing these domains often leads to deregulation of histone lysine methylation, leading to various diseases, most notably, cancer.
We work with the Structural Genomics Consortium (SGC) to develop structure-based potent, selective, cell-active small molecule inhibitors of individual epigenetic regulatory proteins, also referred to as chemical probes. Chemical probes are highly complementary to genetic methods and more closely mimic strategies for therapeutic translation. We are also expanding our chemical probe repertoire to include proximity inducing tool compounds such as proteolysis-targeting chimeras, or PROTACs, which hijack cellular machinery to selectively degrade target epigenetic regulators. Proximity inducing compounds are an exciting new drug modality, especially for proteins that are difficult to modulate with traditional competitive activity-based inhibitors alone.
Target 2035
The majority of the human proteome is either understudied or unstudied, referred to as the ‘Dark Proteome’. Despite the importance of many of these proteins in different human diseases, research tends to focus on targets with well-defined structures and functions. Without the proper tools and resources to study these proteins, the scientific community will remain focused on proteins that have already been well-characterized, leaving a major gap in our knowledge of protein function.
Working with the SGC, our lab has helped to initiate Target 2035, an ambitious project to develop pharmacological modulators for every druggable protein in the human proteome. This requires novel screening strategies as well as the integration of biophysical, structural, biochemical, and cellular assays to identify and characterize small molecule ligands in vitro and validate interactions within cells. Highly pure and stable recombinant proteins are the foundation of these studies. We are working with data scientists and computational biologists/chemists to leverage such data across thousands of proteins to enable machine-learning (ML) algorithms to help change this phase of chemical probe and drug discovery into a largely computational enterprise in the future.
NMR Spectroscopy and Integrated Structural Biology for Cancer Drug Discovery
NMR spectroscopy, X-ray crystallography and cryogenic electron microscopy (cryo-EM) are the common techniques used to determine the 3-dimensional structure of proteins. We have developed NMR analysis resources such as ABACUS, a protocol that analyzes networks of J-correlated spectral peptide-linked peaks and NOE spectral peaks combined with a fragment monte carlo (FMC) procedure to sequence-specifically assign the backbone and side-chain resonances of proteins. To date, this method had been used to solve over 85 protein structures deposited in the PDB. The ABACUS protocol is available for download here.
We also employ X-ray crystallography, small angle X-ray scattering (SAXS), and biophysical methods (SPR, BLI, SEC-MALS, etc.) as tools to characterize multidomain proteins and multiprotein complexes with hybrid computational strategies. We collaborate with several groups within the Princess Margaret Cancer Centre and the Structural Genomics Consortium (SGC) to enable the discovery of novel protein-protein interactions and perform follow-up characterization. This includes high-level proteomics to generate interactome maps and assess changes in the proteome upon epigenetic or chemical modulation, cellular experiments and bioinformatic analyses to assess changes in epigenetics and chromatin dynamics, and cancer models to evaluate the targetability of proteins in an oncogenic context.

Cheryl H Arrowsmith, PhD

Related Links

Search form

Cheryl H Arrowsmith, PhD

Related Links