Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality
Open accessAbstract
The past 20 years have seen many advances in our understanding of protein-protein interactions (PPIs) and how to target them with small-molecule therapeutics. In 2004, we reviewed some early successes; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets. Surprisingly, many of these PPI clinical candidates have efficiency metrics typical of "lead-like" or "drug-like" molecules and are orally available. Successful discovery efforts have integrated multiple disciplines and make use of all the modern tools of target-based discovery-structure, computation, screening, and biomarkers. PPIs become progressively more challenging as the interfaces become more complex, i.e., as binding epitopes are displayed on primary, secondary, or tertiary structures. Here, we review the last 10 years of progress, focusing on the properties of PPI inhibitors that have advanced to clinical trials and prospects for the future of PPI drug discovery.
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There are three different classes of PPI: short continuous peptide epitopes, secondary structural epitopes, and tertiary structural epitopes.
“Generally, there are three different classes of PPI: short continuous peptide epitopes, secondary structural epitopes, and tertiary structural epitopes.”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [24]
PPIs have relatively large and amorphous interfaces, rather than small and well-defined crevices.
“PPIs have relatively large and amorphous interfaces, rather than small and well-defined crevices.”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [24]
Development of molecules targeting PPIs has been challenging compared with targeting enzymes or receptors.
“Compared with targeting enzymes or receptors, however, the development of molecules targeting PPIs has been challenging [22–24].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [24]
In tertiary structure of epitopes, the binding interface is not continuous and requires multiple sites to form the PPI interface.
“In the tertiary structure of epitopes, the binding interface is not continuous and requires multiple sites to form the PPI interface [24].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [24]
Inhibition of protein-protein interactions has proved challenging but feasible.
“The inhibition of PPIs has arguably received more attention in the past and has proved to be challenging but still feasible.2,3”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [3]
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- Authors
- Arkin, M. R., Tang, Y., & Wells, J. A.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Arkin, Michelle R.
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 21
- Issue
- 9
- Pages
- 1102-1114
- ISSN
- 1074-5521 (ISSN-L)
- PMC
- PMC4179228
- OpenAlex
- W2041755933
- Cited by
- 1,065
- References
- 116
- Citations by year
- 2026: 80 · 2025: 62 · 2024: 57 · 2023: 55 · 2022: 80 · 2021: 108 · 2020: 106 · 2019: 103 · 2018: 111 · 2017: 106 · 2016: 109 · 2015: 86 · 2013: 1
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R21AG046526, AG046526)
- National Cancer Institute (CA136779, R01CA136779)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- protein-protein interaction, small molecule inhibitors, PPI inhibitors, drug discovery, clinical trials, target-based drug discovery, binding epitope, oral bioavailability, structure-based drug design, computational screening, biomarkers
- MeSH terms
- Allosteric Regulation, Binding Sites, Humans, Peptides, Proteins, Protein Structure, Secondary, Protein Structure, Tertiary, HIV Integrase, Apoptosis Regulatory Proteins, Protein Interaction Domains and Motifs, Small Molecule Libraries, Protein Interaction Maps
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