Evidence map›Paper›PMID 41454526›Full record

ArticleAngewandte Chemie (International ed. in English)2026

Discovery of a First-in-Class Covalent Allosteric SHP1 Inhibitor with Immunotherapeutic Activity.

Zihan Qu, Frederick Nguele Meke, Zheng Zhang, Aaron D Krabill, Christine S Muli, Brenson A Jassim, Jiajun Dong, Quyen D Nguyen, Yunpeng Bai, Jinyue Li and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Angewandte Chemie (International ed. in English), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing 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

4 citing papers in PubMed.

  1. Review
  2. Review
  3. Article
  4. Review
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

17 authors.

Zihan Qu *James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana, 47907, USA.
Frederick Nguele Meke *Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
Zheng ZhangDepartment of Biochemistry, Purdue University, 175 South University Street, West Lafayette, Indiana, 47907, USA.
Aaron D KrabillBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
Christine S MuliBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
Brenson A JassimBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
Jiajun DongBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
Quyen D NguyenJames Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana, 47907, USA.
Yunpeng BaiBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
Jinyue LiJames Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana, 47907, USA.
Yiming MiaoBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
Bardia AsadiBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
Levi M JohnsonJames Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana, 47907, USA.
Jinmin MiaoBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
Darci J TraderBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
W Andy TaoJames Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana, 47907, USA.
Zhong-Yin ZhangJames Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana, 47907, USA.ORCID 0000-0001-5527-7910

Funding

Structural Biology CoreU54AG065181 · NIA · INDIANA UNIVERSITY INDIANAPOLIS · PI Bruce T Lamb, Alan D. Palkowitz · 2019 to 2026
$61.3M
Transgenic Mouse Core Facility Shared Resource (TMCF-SR)P30CA023168 · NCI · PURDUE UNIVERSITY WEST LAFAYETTE · PI ANDREW D MESECAR · 1985 to 2026
$43.4M
Structure/Function of Protein Tyrosine PhosphatasesR01CA069202 · NCI · YESHIVA UNIVERSITY · PI Zhong-Yin Zhang · 1996 to 2026
$7.3M
Dissecting signaling pathways and seeking EV phosphoproteins as novel biomarkers for Alzheimer's DiseaseRF1AG064250 · NIA · PURDUE UNIVERSITY · PI TAO, W. ANDY · 2020 to 2021
$1.7M
NCI NIH HHS P30 CA023168NCI NIH HHS R01 CA069202NIA NIH HHS RF1 AG064250NIA NIH HHS U54 AG065181NIH HHS NIH 3RF1AG064250NIH HHS NIH RO1CA069202NIH HHS U54AG065181
6 · The paper itself

Abstract

Src homology 2 domain-containing phosphatase 1 (SHP1), encoded by PTPN6, is a key intracellular mediator of inhibitory immune signals. SHP1 is garnering attention as a potential immunotherapeutic target since SHP1 deletion elicits strong antitumor activity by boosting both innate and adaptive immunity. Unfortunately, no quality SHP1 inhibitor exists to demonstrate its translatability owing to the challenges posed by the chemistry of the phosphatase active site. Herein, we describe the discovery of a first-in-class, phenyl chloroacetamide-based covalent allosteric SHP1 inhibitor M029 through covalent fragment screening and multiparameter optimization. M029 inactivates SHP1 by covalently binding to a non-conserved and cryptic Cys480 far away from the active site, thus uncovering a novel allosteric mechanism for SHP1 inhibition. In addition, M029 is highly selective for SHP1 and exhibits robust cellular target engagement. Importantly, M029 is orally active and blocks tumor progression in a syngeneic cancer model by activating natural killer cells and cytotoxic CD8

Indexed as

Drug DiscoveryEnzyme InhibitorsImmunotherapyProtein Tyrosine Phosphatase, Non-Receptor Type 6AcetamidesAllosteric RegulationAnimalsHumansMiceMolecular StructureStructure-Activity RelationshipAcetamidesEnzyme InhibitorsProtein Tyrosine Phosphatase, Non-Receptor Type 6PTPN6 protein, humanAllosteric inhibitionCovalent inhibitorsImmunotherapyLigandable cysteineProtein tyrosine phosphatases

Identifiers

PMID41454526
PMCPMC12833730

What OpenQuestion holds

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LicenceCC BY
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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.