Evidence map›Paper›PMID 40661463›Full record

ArticlebioRxiv : the preprint server for biology2025

Phosphorylation-inducing chimera rewires oncogenic kinase to trigger apoptosis.

Manuel L Merz, Veronika M Shoba, Rajaiah Pergu, Zachary C Severance, Dhanushka N P Munkanatta Godage, Arghya Deb, Hui Si Kwok, Prashant Singh, Sameek Singh, Jonathan B Allen and 16 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. 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

5 · Who and what money

Authors and funding

26 authors.

Manuel L MerzChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Veronika M ShobaChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Rajaiah PerguChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Zachary C SeveranceChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Dhanushka N P Munkanatta GodageChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Arghya DebChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Hui Si KwokDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
Prashant SinghChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Sameek SinghChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jonathan B AllenDepartment of Chemistry, Boston University, Boston, MA 02215, USA.
Wenzhi TianChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Pallavi M GosaviDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
Santosh K ChaudharyChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Viktoriya AnokhinaChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Ellen L WeisbergDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
N Connor PayneDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
Yao HeBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Reilly OsadcheyDepartment of Chemistry, Boston University, Boston, MA 02215, USA.
Mrinal ShekharCenter for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Ralph MazitschekBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Matthew G ReesBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Jennifer A RothBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Qiang CuiDepartment of Chemistry, Boston University, Boston, MA 02215, USA.
James D GriffinDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Brian B LiauDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
Amit ChoudharyChemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Funding

TYROSINE KINASE ONCOGENESIS IN MYELOID LEUKEMIAP01CA066996 · NCI · DANA-FARBER CANCER INSTITUTE · PI SCOTT A ARMSTRONG · 1996 to 2026
$52.5M
Computational Analysis of Enzyme Catalysis and RegulationR35GM141930 · NIGMS · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · PI Qiang Cui · 2021 to 2026
$2.7M
Development of platforms for sorting, production, editing of beta cellsR01DK132900 · NIDDK · BROAD INSTITUTE, INC. · PI Amit Choudhary, Neal Krishna Devaraj · 2023 to 2026
$2.6M
Chemical approaches for precision genome editingR01GM137606 · NIGMS · BROAD INSTITUTE, INC. · PI CHOUDHARY, AMIT · 2021 to 2024
$1.5M
Development of synthetic gene drives using small moleculesR01GM132825 · NIGMS · BRIGHAM AND WOMEN'S HOSPITAL · PI AKBARI, OMAR SULTAN, CHOUDHARY, AMIT · 2019 to 2022
$1.4M
Development of phosphorylation editing chimeras using kinase inhibitorsR21AI178690 · NIAID · BROAD INSTITUTE, INC. · PI CHOUDHARY, AMIT · 2024 to 2025
$462k
NCI NIH HHS P01 CA066996NIAID NIH HHS R21 AI178690NIDDK NIH HHS R01 DK132900NIGMS NIH HHS R01 GM132825NIGMS NIH HHS R01 GM137606NIGMS NIH HHS R35 GM141930
6 · The paper itself

Abstract

Hyperactive enzymes drive the pathology of several diseases, and classically, "occupancy-driven" drugs (e.g., active site or allosteric inhibitors) are used to target these enzymes. However, the stoichiometric nature of such inhibitors and the emergence of resistance highlight the need for new modalities. Here, we report a Phosphorylation-Inducing Chimeric Small molecule (PHICS) that rewires the hyperactivity of an oncogenic kinase, BCR-ABL, to phosphorylate its active site residue. Molecular dynamics simulations suggest this phosphorylation inhibits BCR-ABL by inducing electrostatic rearrangements of its active site. This "event-driven" mechanism selectively induces apoptosis of BCR-ABL-dependent cancer cells at substoichiometric concentrations (vs. stoichiometric concentrations of occupancy-driven drugs). Furthermore, PHICS is effective on other oncogenic ABL fusions or clinically observed resistance mutations, including to occupancy-driven drugs with the same binding site as PHICS, pointing to the orthogonality of 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 modalities.

Indexed as

BCR-ABLCRISPR-suppressor scanningevent-driven pharmacologyinduced proximityPHICSphosphorylationresistance development

Identifiers

PMID40661463
PMCPMC12259158

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
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 OpenQuestion graph.