Evidence map›Paper›PMID 37453329›Full record

ArticleEuropean journal of medicinal chemistry2023

An electrophilic fragment screening for the development of small molecules targeting caspase-2.

Matthew E Cuellar, Mu Yang, Surendra Karavadhi, Ya-Qin Zhang, Hu Zhu, Hongmao Sun, Min Shen, Matthew D Hall, Samarjit Patnaik, Karen H Ashe and 2 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in European journal of medicinal chemistry, 2023. 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
0.8field-weighted citation impact, top 27% of its field
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, 5 citations in OpenAlex.

  1. Article
  2. Review
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

12 authors at 2 institutions in 2 countries.

Matthew E CuellarDepartment of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN, 55414, USA.
Mu YangDepartment of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN, 55414, USA.
Surendra KaravadhiNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Ya-Qin ZhangNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Hu ZhuNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Hongmao SunNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Min ShenNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Matthew D HallNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Samarjit PatnaikNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Karen H AsheDepartment of Neurology, University of Minnesota, 2101 6th Street SE, Minneapolis, MN, 55455, USA.
Michael A WaltersDepartment of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN, 55414, USA. Electronic address: mwalters@umn.edu.
Steffen PockesDepartment of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN, 55414, USA; Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany. Electronic address: steffen.pockes@ur.de.
National Institutes of Health · USUniversity of Minnesota · US

Funding

Caspase-2 Probe CompoundsR01AG062199 · NIA · UNIVERSITY OF MINNESOTA · PI ASHE, KAREN H, WALTERS, MICHAEL A. · 2019 to 2023
$3.9M
NIA NIH HHS R01 AG062199
6 · The paper itself

Abstract

Recent Alzheimer's research has shown increasing interest in the caspase-2 (Casp2) enzyme. However, the available Casp2 inhibitors, which have been pentapeptides or peptidomimetics, face challenges for use as CNS drugs. In this study, we successfully screened a 1920-compound chloroacetamide-based, electrophilic fragment library from Enamine. Our two-point dose screen identified 64 Casp2 hits, which were further evaluated in a ten-point dose-response study to assess selectivity over Casp3. We discovered compounds with inhibition values in the single-digit micromolar and sub-micromolar range, as well as up to 32-fold selectivity for Casp2 over Casp3. Target engagement analysis confirmed the covalent-irreversible binding of the selected fragments to Cys320 at the active site of Casp2. Overall, our findings lay a strong foundation for the future development of small-molecule Casp2 inhibitors.

Indexed as

Caspase 2Caspase InhibitorsCaspase 3Catalytic DomainCaspase 2Caspase 3Caspase Inhibitors

Identifiers

PMID37453329
PMCPMC10529632
OpenAlexW4383955236

What OpenQuestion holds

Textmetadata
LicenceTDM
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.