Evidence map›Paper›PMID 42421462›Full record

ArticleDrug development research2026

A Tale of Two Mechanisms: The p53 Modulator COTI-2 Is a Zn Metallochaperone.

İrem Şimşek, Farsheed Shahbazi-Raz, Michael J Krause, Azam Mohammadzadeh, Maryam Kosar, Peihan Xu, Samra Khan, Olena Tykhoniuk, Ashley DaDalt, Deya'a Almasri and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Drug development research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

İrem ŞimşekDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Farsheed Shahbazi-RazDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Michael J KrauseDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Azam MohammadzadehDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Maryam KosarDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Peihan XuDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Samra KhanDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.ORCID https://orcid.org/0000-0003-4922-0381
Olena TykhoniukDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Ashley DaDaltDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Deya'a AlmasriDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Lara K WatanabeDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Kaitlyn BreaultDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
John J HaywardDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Fraser S PickDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
Richard L HoAmaro Therapeutics, New York, New York, USA.
Jeremy M RawsonDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
John F TrantDepartment of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.ORCID https://orcid.org/0000-0002-4780-4968

Funding

Natural Sciences and Engineering Research Council of Canada 2018-06338Natural Sciences and Engineering Research Council of Canada ALLRP- 555689-20
6 · The paper itself

Abstract

Mutations in, or misregulation of, Tp53 are found in approximately 50% of all cancers. p53 functions by ensuring that cells with irretrievably damaged DNA undergo apoptosis. Tp53 mutations often induce conformational changes that inhibit activity; however, small-molecule chaperones could theoretically restore conformation and activity. COTI-2, a thiosemicarbazone with orphan-drug status for ovarian cancer, has proven an effective cytotoxic agent against various cancer cell lines in vitro, exhibited efficacy in vivo, and has demonstrated a good safety profile in Phase 1b human clinical trials. The proposed mechanism, direct engagement and refolding of mutant p53, has been supported by a combination of cell-based assays and transcriptomics data. Through a combination of experimental and computational approaches, we demonstrate that this is an unlikely mechanism of action, and that COTI-2 instead likely acts as a selective, well-tolerated, zinc chaperone to replace zinc ions lost to p53 mutants' deficient zinc-binding.

Indexed as

Antineoplastic AgentsMetallochaperonesThiosemicarbazonesTumor Suppressor Protein p53ZincAnimalsApoptosisCell Line, TumorHumansMutationAntineoplastic AgentsMetallochaperonesThiosemicarbazonesTP53 protein, humanTumor Suppressor Protein p53Zincapoptosischemotherapymetallochaperonepersonalized medicinerestoration‐of‐function

Identifiers

PMID42421462
PMCPMC13347104

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.