Evidence map›Paper›PMID 40626960›Full record

ArticleAngewandte Chemie (International ed. in English)2025

Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders.

Zhe Zhuang, Woong Sub Byun, Zuzanna Kozicka, Katherine A Donovan, Brendan G Dwyer, Abby M Thornhill, Hannah M Jones, Zixuan Jiang, Xijun Zhu, Eric S Fischer and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Angewandte Chemie (International ed. in English), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing 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

9 citing papers in PubMed.

  1. Review
  2. Covalent Reprogramming of Kinase Binders to Modulate Protein Abundance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Article
  3. Review
  4. Article
  5. Article
  6. Review
  7. Review
  8. Article
  9. Covalent Reprogramming of Kinase Binders to Modulate Protein Homeostasis.bioRxiv : the preprint server for biology · 2025
    Article
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

12 authors.

Zhe Zhuang *Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Woong Sub Byun *Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Zuzanna KozickaFriedrich Miescher Institute for Biomedical Research, Basel, 4056, Switzerland.
Katherine A DonovanDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Brendan G DwyerDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Abby M ThornhillDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Hannah M JonesDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Zixuan JiangDepartment of Chemistry, Stanford University, Stanford, CA, 94305, USA.
Xijun ZhuDepartment of Chemistry, Stanford University, Stanford, CA, 94305, USA.
Eric S FischerDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Nicolas H ThomäFriedrich Miescher Institute for Biomedical Research, Basel, 4056, Switzerland.
Nathanael S GrayDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA.ORCID 0000-0001-5354-7403

Funding

Degrading therapeutically important kinases using small moleculesR01CA218278 · NCI · STANFORD UNIVERSITY · PI Eric Sebastian Fischer, NATHANAEL Schiander GRAY · 2019 to 2026
$4.6M
Development of a generalizable chemo-proteomics screening platform for small molecule degraders applied to HDACsR01CA262188 · NCI · DANA-FARBER CANCER INST · PI FISCHER, ERIC SEBASTIAN · 2022 to 2025
$1.8M
500 MHz NMR Spectrometer System with High Sensitivity Cryoprobe and Automated Sample Changer for Biochemical ResearchS10OD028697 · OD · STANFORD UNIVERSITY · PI BURNS, NOAH ZACHARY · 2020 to 2020
$709k
Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education RS-2024-00410290ESR Marie Curie-Skłodowska fellowship UbiCODE 765445European Research CouncilEuropean Union's H2020 Research Program 884331NCI NIH HHS R01 CA218278NCI NIH HHS R01 CA262188NIH HHS R01CA2144608NIH HHS R01CA218278NIH HHS R01CA262188NIH HHS S10 OD028697NIH High End Instrumentation 1S10OD028697-01Stanford Chemical and Systems Biology and Stanford Cancer InstituteSwiss National Science Foundation 310030_214852Swiss National Science Foundation SNF 310030_301206
6 · The paper itself

Abstract

Targeted protein degradation (TPD) is an emerging therapeutic approach for the selective elimination of disease-related proteins. While molecular glue degraders exhibit drug-like properties, their discovery has traditionally been serendipitous and often requires post hoc rationalization. In this study, we demonstrate the rational, mechanism-guided design of molecular glue degraders using gluing moieties. Building on established principles, by appending a chemical gluing moiety to several small molecule inhibitors, we successfully transformed them into degraders, obviating the need for a specific E3 ubiquitin ligase recruiter. Specifically, we found that incorporating a hydrophobic aromatic ring or a double bond into a cyclin-dependent kinase 12 and 13 (CDK12/13) dual inhibitor enabled the recruitment of DNA damage-binding protein 1 (DDB1), thereby transforming a high-molecular-weight bivalent CDK12 degrader into a potent monovalent CDK12/13 molecular glue degrader. We also showcase that attaching a cysteine-reactive warhead to a bromodomain-containing protein 4 (BRD4) inhibitor converts it into a degrader by recruiting the DDB1 and CUL4-associated factor 16 (DCAF16) E3 ligase.

Indexed as

Cell Cycle ProteinsCyclin-Dependent KinasesDrug DesignProtein Kinase InhibitorsTranscription FactorsBromodomain Containing ProteinsDNA-Binding ProteinsHumansMolecular StructureProteolysisBRD4 protein, humanBromodomain Containing ProteinsCDK12 protein, humanCell Cycle ProteinsCyclin-Dependent KinasesDDB1 protein, humanDNA-Binding ProteinsProtein Kinase InhibitorsTranscription FactorsBromodomain‐containing protein 4Cyclin‐dependent kinase 12/13Molecular glueTargeted protein degradation

Identifiers

PMID40626960
PMCPMC12831537

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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.