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Discovery of a Potent and Selective Naphthyridine-Based Chemical Probe for Casein Kinase 2

2023· article· en· W4324132784 on OpenAlexfundno aff
Zachary W. Davis‐Gilbert, Andreas Krämer, James E. Dunford, Stefanie Howell, Filiz Senbabaoglu, Carrow I. Wells, Frances M. Bashore, Tammy M. Havener, Jeffery L. Smith, Mohammad Anwar Hossain, Udo Oppermann, David H. Drewry, Alison D. Axtman

Bibliographic record

VenueACS Medicinal Chemistry Letters · 2023
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicProtein Kinase Regulation and GTPase Signaling
Canadian institutionsnot available
FundersEshelman Institute for Innovation, University of North Carolina at Chapel HillNational Institute of Diabetes and Digestive and Kidney DiseasesGenentechInnovative Medicines InitiativeCancer Research UKCanada Foundation for InnovationOntario Genomics InstituteEuropean Federation of Pharmaceutical Industries and AssociationsFondation LeducqMerck KGaANational Institutes of HealthOntario GenomicsFundação de Amparo à Pesquisa do Estado de São PauloGenome CanadaU.S. Department of DefenseChordoma FoundationPfizerFundação Amazônia Paraense de Amparo à PesquisaMcGill UniversityNorth Carolina Biotechnology CenterBayer
KeywordsCasein kinase 2KinomeChemical biologySmall moleculeChemistrySelectivityDrug discoveryKinaseCombinatorial chemistryBiochemistryComputational biologyProtein kinase ABiologyMitogen-activated protein kinase kinase

Abstract

fetched live from OpenAlex

High Resolution Image Download MS PowerPoint Slide Naphthyridine-based inhibitors were synthesized to yield a potent and cell-active inhibitor of casein kinase 2 (CK2). Compound 2 selectively inhibits CK2α and CK2α′ when profiled broadly, thereby making it an exquisitely selective chemical probe for CK2. A negative control that is structurally related but lacks a key hinge-binding nitrogen ( 7 ) was designed on the basis of structural studies. Compound 7 does not bind CK2α or CK2α′ in cells and demonstrates excellent kinome-wide selectivity. Differential anticancer activity was observed when compound 2 was profiled alongside a structurally distinct CK2 chemical probe: SGC-CK2-1. This naphthyridine-based chemical probe ( 2 ) represents one of the best available small molecule tools with which to interrogate biology mediated by CK2.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

How this classification was reachedexpand

Full frame distilled prediction

Teacher imitation

Not calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.

metaresearch head score (Codex)0.000
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Bench or experimental · Consensus signal: Bench or experimental
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.007
Threshold uncertainty score0.613

Codex and Gemma teacher scores by category

CategoryCodexGemma
Metaresearch0.0000.000
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0000.000
Bibliometrics0.0000.000
Science and technology studies0.0000.000
Scholarly communication0.0000.000
Open science0.0000.000
Research integrity0.0000.000
Insufficient payload (model declined to judge)0.0000.000

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.

Opus teacher head0.010
GPT teacher head0.245
Teacher spread0.234 · how far apart the two teachers sit on this one work
Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one teacher head, not a consensus.

The models applied no category: nothing in the taxonomy fit this work.
Study designBench or experimental
Domainnot available
GenreEmpirical

How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".

Quick stats

Citations16
Published2023
Admission routes1
Has abstractyes

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