Cited by 90Cell death mechanisms and regulationComputational Drug Discovery MethodsChemical Synthesis and Analysis

Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP

Chessari, Gianni, Buck, Ildiko M., Day, James E. H., Day, Philip J., Iqbal, Aman, Johnson, Christopher N., Lewis, Edward J., Martins, Vanessa +11 more·2015·Journal of Medicinal Chemistry

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.

Integrity signals

Registry

Crossref · 10.1021/acs.jmedchem.5b00706

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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
Venue
Journal of Medicinal Chemistry
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review