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Record W4243756908 · doi:10.26434/chemrxiv.12616178

A Chemical Probe for Dark Kinase STK17B Derives its Potency and High Selectivity Through a Unique P-loop Conformation

2020· preprint· en· W4243756908 on OpenAlexafffund
Alfredo Picado, A. Chaikuad, Carrow I. Wells, Safal Shrestha, William J. Zuercher, Julie E. Pickett, Frank E. Kwarcinski, Parvathi Sinha, Chandi de Silva, Reena Zutshi, Shubin Liu, Natarajan Kannan, Stefan Knapp, David H. Drewry, Timothy M. Willson

Bibliographic record

VenueChemRxiv · 2020
Typepreprint
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicCancer therapeutics and mechanisms
Canadian institutionsStructural Genomics Consortium
FundersDeutsches Elektronen-SynchrotronDeutschen Konsortium für Translationale KrebsforschungNovartis PharmaNational Institutes of HealthMinistero dello Sviluppo EconomicoUniversidade Estadual de CampinasMerck KGaAOntario Ministry of Economic Development and InnovationGenome CanadaFundação de Amparo à Pesquisa do Estado de São PauloLineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillDiamond Light SourcePfizer
KeywordsChemistryKinaseSelectivityStereochemistrySalt bridgePyrimidineBiochemistryGeneMutant

Abstract

fetched live from OpenAlex

We present the discovery of thieno[3,2-<i>d</i>]pyrimidine <b>SGC-STK17B-1</b> (<b>11s</b>), a high-quality chemical probe for this understudied “dark” kinase. <b>11s</b> is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of <b>11s</b> and related thieno[3,2-<i>d</i>]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor.

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 categoriesMeta-epidemiology (narrow)
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 score0.222
Threshold uncertainty score1.000

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 head0.025
GPT teacher head0.274
Teacher spread0.250 · 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.

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

Citations2
Published2020
Admission routes2
Has abstractyes

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