Reimagining Druggability Using Chemoproteomic Platforms
Abstract
One of the biggest bottlenecks in modern drug discovery efforts is in tackling the undruggable proteome. Currently, over 85% of the proteome is still considered undruggable because most proteins lack well-defined binding pockets that can be functionally targeted with small molecules. Tackling the undruggable proteome necessitates innovative approaches for ligand discovery against undruggable proteins as well as the development of new therapeutic modalities to functionally manipulate proteins of interest. Chemoproteomic platforms, in particular activity-based protein profiling (ABPP), have arisen to tackle the undruggable proteome by using reactivity-based chemical probes and advanced quantitative mass spectrometry-based proteomic approaches to enable the discovery of "ligandable hotspots" or proteome-wide sites that can be targeted with small-molecule ligands. These sites can subsequently be pharmacologically targeted with covalent ligands to rapidly discover functional or nonfunctional binders against therapeutic proteins of interest. Chemoproteomic approaches have also revealed unique insights into ligandability such as the discovery of unique allosteric sites or intrinsically disordered regions of proteins that can be pharmacologically and selectively targeted for biological modulation and therapeutic benefit. Chemoproteomic platforms have also expanded the scope of emerging therapeutic modalities for targeted protein degradation and proteolysis-targeting chimeras (PROTACs) through the discovery of several new covalent E3 ligase recruiters. Looking into the future, chemoproteomic approaches will unquestionably have a major impact in further expansion of existing efforts toward proteome-wide ligandability mapping, targeted ligand discovery efforts against high-value undruggable therapeutic targets, further expansion of the scope of targeted protein degradation platforms, the discovery of new molecular glue scaffolds that enable unique modulation of protein function, and perhaps most excitingly the development of next-generation small-molecule induced-proximity-based therapeutic modalities that go beyond degradation. Exciting days lie ahead in this field as chemical biology becomes an increasingly major driver in drug discovery, and chemoproteomic approaches are sure to be a mainstay in developing next-generation therapeutics.
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Chemoproteomic platforms enable rapid target identification and selectivity profiling of covalent ligands.
“This ‘electrophile-first’ approach is partly facilitated by the development of chemoproteomic platforms that enable rapid target identification and selectivity profiling of covalent ligands14–18.”
From Advances in covalent drug discovery (2022) · cites this paper as [14]
Covalent drug discovery platforms have facilitated expansion of targeted protein degradation by enabling discovery of covalent recruiters against E3 ubiquitin ligases.
“Covalent drug discovery platforms have facilitated the expansion of targeted protein degradation approaches by enabling the discovery of covalent recruiters against E3 ubiquitin ligases14,187–193.”
From Advances in covalent drug discovery (2022) · cites this paper as [14]
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Self-citation
- Authors
- Spradlin, J. N., Zhang, E., & Nomura, D. K.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Nomura, Daniel K.
- Venue
- Accounts of Chemical Research
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-03-18
- Volume
- 54
- Issue
- 7
- Pages
- 1801-1813
- ISSN
- 0001-4842 (ISSN-L)
- 1520-4898
- OpenAlex
- W3136460174
- Cited by
- 176
- References
- 60
- Citations by year
- 2026: 31 · 2025: 48 · 2024: 41 · 2023: 28 · 2022: 22 · 2021: 6
- FWCI
- 9.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Accounts of Chemical Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novartis
- National Cancer Institute (F31CA239327, F99CA253717, R01CA240981)
- Mark Foundation For Cancer Research
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- chemoproteomics, activity-based protein profiling, PROTACs, targeted protein degradation, molecular glues, allosteric site, intrinsically disordered regions, covalent ligands, drug discovery
- MeSH terms
- Humans, Ligands, Proteome, Proteomics, Drug Discovery, Proteolysis
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