Evidence map›Paper›PMID 39232360›Full record

ArticleEuropean journal of medicinal chemistry2024

Discovery of selective Orai channel blockers bearing an indazole or a pyrazole scaffold.

Elisa Liardo, Anh-Tuan Pham, Amanda F Ghilardi, Tetyana Zhelay, Kalina Szteyn, Naga Lakshmi Gandi, Anil Ekkati, Steffi Koerner, J Ashot Kozak, Lijun Sun

Abstract read
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In one paragraph

Article in European journal of medicinal chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

10 authors.

Elisa LiardoCenter for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
Anh-Tuan PhamCenter for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
Amanda F GhilardiCenter for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
Tetyana ZhelayDepartment of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine and College of Science and Mathematics, Wright State University, Dayton, OH, 45435, USA.
Kalina SzteynDepartment of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine and College of Science and Mathematics, Wright State University, Dayton, OH, 45435, USA.
Naga Lakshmi GandiDepartment of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine and College of Science and Mathematics, Wright State University, Dayton, OH, 45435, USA.
Anil EkkatiCenter for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
Steffi KoernerCenter for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
J Ashot KozakDepartment of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine and College of Science and Mathematics, Wright State University, Dayton, OH, 45435, USA. Electronic address: juliusz.kozak@wright.edu.
Lijun SunCenter for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. Electronic address: lsun1@bidmc.harvard.edu.

Funding

SPECIAL ASSAY COREP30DK036836 · NIDDK · JOSLIN DIABETES CENTER · PI ROHIT N. KULKARNI · 1986 to 2026
$50.5M
TRPM7 and Cellular pHR01AI114804 · NIAID · WRIGHT STATE UNIVERSITY · PI KOZAK, JULIUSZ ASHOT · 2015 to 2019
$1.8M
Sodium Influx Assay for Measurement of TRPM7 Channel Activity in Intact CellsR21AI144337 · NIAID · WRIGHT STATE UNIVERSITY · PI KOZAK, JULIUSZ ASHOT · 2020 to 2021
$409k
NIAID NIH HHS R01 AI114804NIAID NIH HHS R21 AI144337NIDDK NIH HHS P30 DK036836
6 · The paper itself

Abstract

The calcium release activated calcium (CRAC) channel is highly expressed in T lymphocytes and plays a critical role in regulating T cell proliferation and functions including activation of the transcription factor nuclear factor of activated T cells (NFAT), cytokine production and cytotoxicity. The CRAC channel consists of the Orai pore subunit and STIM (stromal interacting molecule) endoplasmic reticulum calcium sensor. Loss of CRAC channel mediated calcium signaling has been identified as an underlying cause of severe combined immunodeficiency (SCID), leading to drastically weakened immunity against infections. Gain-of-function mutations in Orai and STIM have been associated with tubular aggregated myopathy (TAM), a skeletal muscle disease. While a number of small molecules have shown activity in inhibiting the CRAC signaling pathway, the usefulness of those tool compounds is limited by their off-target activity against TRPM4 and TRPM7 ion channels, high lipophilicity, and a lack of understanding of their mechanism of action. We report structure-activity relationship (SAR) studies that resulted in the characterization of compound 4k [1-(cyclopropylmethyl)-N-(3-fluoropyridin-4-yl)-1H-indazole-3-carboxamie] as a fast onset, reversible, and selective CRAC channel blocker. 4k fully blocked the CRAC current (IC

Indexed as

Calcium Channel BlockersIndazolesPyrazolesCalcium Release Activated Calcium ChannelsDose-Response Relationship, DrugDrug DiscoveryHumansMolecular StructureORAI1 ProteinStructure-Activity RelationshipCalcium Channel BlockersCalcium Release Activated Calcium ChannelsIndazolesORAI1 ProteinPyrazolesAutoimmune diseasesCalcium release activated calcium (CRAC) channelNuclear factor of activated T cells (NFAT)Orai blockersStore-operated calcium entry (SOCE)Transient receptor potential melastatin 4 and 7 (TRPM4 and TRPM7) channels

Identifiers

PMID39232360
PMCPMC12993747

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Registered trials

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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.