Proximity-induced rewiring of oncogenic kinase triggers apoptosis Article Swipe
Maximilian Merz
,
Veronika M. Shoba
,
Rajaiah Pergu
,
Zachary C. Severance
,
Dhanushka N. P. Munkanatta Godage
,
Arghya Deb
,
Hui Si Kwok
,
Prashant Singh
,
Sameek Singh
,
John Allen
,
Wenzhi Tian
,
Pallavi M. Gosavi
,
Santosh Kumar Chaudhary
,
Viktoriya Anokhina
,
Ellen Weisberg
,
N. Connor Payne
,
Xiaotong Yao
,
Rohil Dhaliwal
,
Mrinal Shekhar
,
Ralph Mazitschek
,
Matthew G. Rees
,
Jennifer A. Roth
,
Qiang Cui
,
Qiang Cui
,
Brian B. Liau
,
Amit Choudhary
,
Amit Choudhary
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.06.13.659082
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.06.13.659082
The active site’s electric field is integral to enzymatic catalysis (e.g., substrate recognition) and nature employs charge-altering post-translational modifications (e.g., phosphorylation) to perturb this electric field and regulate enzymes. A chromosomal translocation converts Abelson kinase (ABL) to BCR-ABL, whose hyperactivity drives several cancers. Here, we developed a small molecule, BRD8833, that induces BCR-ABL phosphorylation, which perturbs its active site’s electric field with loss of hyperactivity. Unlike “occupancy-driven” inhibitors that require stoichiometric concentrations, BRD8833 operates through an event-driven, substoichiometric mechanism by inducing proximity between two BCR-ABL molecules to trigger the inhibitory phosphorylation and selective apoptosis of BCR-ABL-dependent cancer cells. Furthermore, BRD8833 is effective against other oncogenic ABL fusions or clinically observed resistance mutations, including those to occupancy-driven drugs with the same binding site as BRD8833, suggesting differences in their resistance mechanisms. These studies lay the foundation for electric-field and “event-driven” modalities to control hyperactive enzymes with orthogonal resistance mechanisms to occupancy-driven drugs. GRAPHICAL ABSTRACT (TOC)
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.06.13.659082
- https://www.biorxiv.org/content/biorxiv/early/2025/06/13/2025.06.13.659082.full.pdf
- OA Status
- green
- References
- 68
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4411297445
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4411297445Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2025.06.13.659082Digital Object Identifier
- Title
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Proximity-induced rewiring of oncogenic kinase triggers apoptosisWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
-
2025-06-13Full publication date if available
- Authors
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Maximilian Merz, Veronika M. Shoba, Rajaiah Pergu, Zachary C. Severance, Dhanushka N. P. Munkanatta Godage, Arghya Deb, Hui Si Kwok, Prashant Singh, Sameek Singh, John Allen, Wenzhi Tian, Pallavi M. Gosavi, Santosh Kumar Chaudhary, Viktoriya Anokhina, Ellen Weisberg, N. Connor Payne, Xiaotong Yao, Rohil Dhaliwal, Mrinal Shekhar, Ralph Mazitschek, Matthew G. Rees, Jennifer A. Roth, Qiang Cui, Qiang Cui, Brian B. Liau, Amit Choudhary, Amit ChoudharyList of authors in order
- Landing page
-
https://doi.org/10.1101/2025.06.13.659082Publisher landing page
- PDF URL
-
https://www.biorxiv.org/content/biorxiv/early/2025/06/13/2025.06.13.659082.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
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https://www.biorxiv.org/content/biorxiv/early/2025/06/13/2025.06.13.659082.full.pdfDirect OA link when available
- Concepts
-
Chimera (genetics), Phosphorylation, Apoptosis, Kinase, Cell biology, Cancer research, Biology, Genetics, GeneTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- References (count)
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68Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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