Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP
Abstract
Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptosis and pro-survival signaling pathways whose deregulation is often associated with tumor genesis and tumor growth. IAPs have been proposed as targets for anticancer therapy, and a number of peptidomimetic IAP antagonists have entered clinical trials. Using our fragment-based screening approach, we identified nonpeptidic fragments binding with millimolar affinities to both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). Structure-based hit optimization together with an analysis of protein-ligand electrostatic potential complementarity allowed us to significantly increase binding affinity of the starting hits. Subsequent optimization gave a potent nonalanine IAP antagonist structurally distinct from all IAP antagonists previously reported. The lead compound had activity in cell-based assays and in a mouse xenograft efficacy model and represents a highly promising start point for further optimization.
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Small-molecule antagonists exploiting the substrate-binding site of IAPs, including non-peptido-mimetic compounds, have been developed with low-nanomolar potency.
“small-molecule antagonists exploiting the substrate-binding site, including non-peptido-mimetic compounds, have been developed with low-nanomolar potency 117,118,119”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [118]
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Targeted protein degradation: expanding the toolbox
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- Authors
- Chessari, G., Buck, I. M., Day, J. E. H., Day, P. J., Iqbal, A., Johnson, C. N., Lewis, E. J., Martins, V., Miller, D., Reader, M., Rees, D. C., Rich, S. J., Tamanini, E., Vitorino, M., Ward, G. A., Williams, P. A., Williams, G., Wilsher, N. E., & Woolford, A. J.-A.
- Affiliations
- Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom
- Corresponding author
- Chessari, Gianni
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-08-07
- Volume
- 58
- Issue
- 16
- Pages
- 6574-6588
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W1011422075
- Cited by
- 90
- References
- 55
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 9 · 2023: 3 · 2022: 7 · 2021: 9 · 2020: 11 · 2019: 16 · 2018: 9 · 2017: 10 · 2016: 7 · 2015: 2
- FWCI
- 4.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- 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
- Keywords
- inhibitor of apoptosis proteins, cIAP1, XIAP, IAP antagonists, fragment-based drug discovery, anticancer drug targets, apoptosis regulation
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Mice, Inbred BALB C, Models, Molecular, Peptide Fragments, Piperazines, Drug Design, Computational Biology, Xenograft Model Antitumor Assays, Cell Proliferation, Inhibitor of Apoptosis Proteins, Mice, X-Linked Inhibitor of Apoptosis Protein, Drug Discovery, High-Throughput Screening Assays
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