Evidence map›Paper›PMID 31757680›Full record

ArticleBioorganic & medicinal chemistry2020

Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization.

Paul A Allegretti, Timothy M Horton, Yassan Abdolazimi, Hannah P Moeller, Benjamin Yeh, Matthew Caffet, Guillermina Michel, Mark Smith, Justin P Annes

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

Article in Bioorganic & medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed
2.9field-weighted citation impact, top 9% 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

16 citing papers in PubMed, 23 citations in OpenAlex.

  1. Article
  2. Review
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  4. Article
  5. Article
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  7. Article
  8. Review
  9. Review
  10. Diabetic Kinome Inhibitors-A New Opportunity for β-Cells Restoration.International journal of molecular sciences · 2021
    Review
  11. Article
  12. Review
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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

9 authors at 1 institution in 1 country.

Paul A AllegrettiDepartment of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
Timothy M HortonDepartment of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA; Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
Yassan AbdolazimiDepartment of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA.
Hannah P MoellerDepartment of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA; Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA.
Benjamin YehDepartment of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA.
Matthew CaffetStanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
Guillermina MichelDepartment of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA.
Mark SmithStanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
Justin P AnnesDepartment of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA. Electronic address: Jannes@stanford.edu.
Stanford University · US

Funding

Stanford Center for Clinical & Translational Education and Research (Spectrum)UL1TR003142 · NCATS · STANFORD UNIVERSITY · PI O'HARA, RUTH M · 2019 to 2023
$45.0M
Spectrum Stanford Center for clinical and Translational Research and EducationUL1TR001085 · NCATS · STANFORD UNIVERSITY · PI CULLEN, MARK RICHARD, GREENBERG, HARRY BERNARD · 2013 to 2017
$37.1M
Stanford Islet Research CoreP30DK116074 · NIDDK · STANFORD UNIVERSITY · PI Holden T. Maecker · 2017 to 2026
$19.5M
Institutional Career Development Core (KL2)KL2TR003143 · NCATS · STANFORD UNIVERSITY · PI ASCH, STEVEN M. · 2019 to 2023
$8.7M
Diabetes, Endocrinology and Metabolism Training GrantT32DK007217 · NIDDK · STANFORD UNIVERSITY · PI Justin Pierce Annes, David Matthew Maahs · 1987 to 2026
$7.2M
Spectrum Stanford Center for clinical and Translational Research and EducationKL2TR001083 · NCATS · STANFORD UNIVERSITY · PI CULLEN, MARK RICHARD, GREENBERG, HARRY BERNARD · 2013 to 2017
$4.9M
Promoting diversity in research careers in diabetes, digestive and kidney diseasesR25DK078381 · NIDDK · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI MATTERS, GAIL L., REEVES, WILLIAM BRIAN · 2007 to 2024
$4.6M
The Role of Adenosine Kinase in Controlling Beta-Cell RegenerationR01DK101530 · NIDDK · STANFORD UNIVERSITY · PI ANNES, JUSTIN PIERCE · 2015 to 2024
$3.8M
Development of Beta-Cell-Targeted Regenerative Therapeutics Using A Novel Prodrug StrategyR01DK119955 · NIDDK · STANFORD UNIVERSITY · PI ANNES, JUSTIN PIERCE · 2019 to 2023
$2.1M
Stanford Chem-H Chemistry/Biology Interface Predoctoral Training ProgramT32GM120007 · NIGMS · STANFORD UNIVERSITY · PI BERTOZZI, CAROLYN · 2016 to 2020
$1.2M
Molecular Pharmacology Training GrantT32GM113854 · NIGMS · STANFORD UNIVERSITY · PI MOCHLY-ROSEN, DARIA · 2015 to 2019
$1.1M
NCATS NIH HHS KL2 TR001083NCATS NIH HHS KL2 TR003143NCATS NIH HHS UL1 TR001085NCATS NIH HHS UL1 TR003142NIDDK NIH HHS P30 DK116074NIDDK NIH HHS R01 DK101530NIDDK NIH HHS R01 DK119955NIDDK NIH HHS R25 DK078381NIDDK NIH HHS T32 DK007217NIGMS NIH HHS T32 GM113854NIGMS NIH HHS T32 GM120007
6 · The paper itself

Abstract

Small molecule stimulation of β-cell regeneration has emerged as a promising therapeutic strategy for diabetes. Although chemical inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is sufficient to enhance β-cell replication, current lead compounds have inadequate cellular potency for in vivo application. Herein, we report the clinical stage anti-cancer kinase inhibitor OTS167 as a structurally novel, remarkably potent DYRK1A inhibitor and inducer of human β-cell replication. Unfortunately, OTS167's target promiscuity and cytotoxicity curtails utility. To tailor kinase selectivity towards DYRK1A and reduce cytotoxicity we designed a library of fifty-one OTS167 derivatives based upon a modeled structure of the DYRK1A-OTS167 complex. Indeed, derivative characterization yielded several leads with exceptional DYRK1A inhibition and human β-cell replication promoting potencies but substantially reduced cytotoxicity. These compounds are the most potent human β-cell replication-promoting compounds yet described and exemplify the potential to purposefully leverage off-target activities of advanced stage compounds for a desired application.

Indexed as

Binding SitesCell ProliferationDyrk KinasesHumansInsulinInsulin-Secreting CellsKineticsMolecular Docking SimulationNaphthyridinesProtein Kinase InhibitorsProtein Serine-Threonine KinasesProtein Structure, TertiaryProtein-Tyrosine KinasesSmall Molecule LibrariesStructure-Activity RelationshipDyrk KinasesInsulinNaphthyridinesProtein Kinase InhibitorsProtein Serine-Threonine KinasesProtein-Tyrosine KinasesSmall Molecule LibrariesDiabetesDual-specificity tyrosine-regulated kinase 1A (DYRK1A)Medicinal chemistryβ-cell regenerationβ-cell replication

Identifiers

PMID31757680
PMCPMC6941846
OpenAlexW2987752990

What OpenQuestion holds

Textmetadata
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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.