Evidence map›Paper›PMID 42130460›Full record

ArticleJournal of medicinal chemistry2026

Targeting a Pleckstrin Homology Domain with a Lysine-Reactive Covalent Binder.

Rebekah M West, Radu Costin Bizga Nicolescu, Paul Brear, James Wagstaff, Beata K Blaszczyk, Tomas Deingruber, Matthew G Sanders, Francisco Javier Pérez-Areales, David R Spring, Marko Hyvönen

Abstract read
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In one paragraph

Article in Journal of medicinal chemistry, 2026. 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.

Rebekah M WestYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.ORCID 0000-0002-8621-7184
Radu Costin Bizga NicolescuYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
Paul BrearDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.ORCID 0000-0002-4045-0474
James WagstaffDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
Beata K BlaszczykDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
Tomas DeingruberYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
Matthew G SandersOncology Targeted Discovery, Oncology R&D, The Discovery Centre, AstraZeneca, Cambridge CB2 0AA, U.K.
Francisco Javier Pérez-ArealesYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.ORCID 0000-0001-9525-9346
David R SpringYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
Marko HyvönenDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.ORCID 0000-0001-8683-4070

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Bruton's Tyrosine Kinase (BTK) is a validated target for hematological malignancies, with numerous FDA-approved inhibitors on the market. Current therapies target the highly conserved ATP binding site and hence limit the therapeutic index given the site's highly conserved nature across the kinome. We explore a novel approach for BTK inhibition by targeting the PH domain-mediated membrane recruitment and activation of BTK. We have identified a fragment which covalently modifies a lysine in the inositol phosphate (PIP3) binding site and inhibits the binding of a soluble PIP3 headgroup analog to the PH domain. Fragment growth and an extensive structure-binding relationship study uncovered 27 crystal structures and a best-in-class analog,

Indexed as

Agammaglobulinaemia Tyrosine KinaseLysinePleckstrin Homology DomainsProtein Kinase InhibitorsBinding SitesCrystallography, X-RayHumansInositol PhosphatesModels, MolecularStructure-Activity RelationshipAgammaglobulinaemia Tyrosine KinaseBTK protein, humanInositol PhosphatesLysineProtein Kinase Inhibitors

Identifiers

PMID42130460
PMCPMC13224087

What Socratic holds

Textmetadata
LicenceCC BY
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 Socratic graph.