Evidence map›Paper›PMID 39753134›Full record

ArticleCell chemical biology2025

Development of an FKBP12-recruiting chemical-induced proximity DNA-encoded library and its application to discover an autophagy potentiator.

Zher Yin Tan, Joel K A Adade, Xiebin Gu, Cody J S Hecht, Michael Salcius, Bingqi Tong, Shuang Liu, Seungmin Hwang, Frédéric J Zécri, Daniel B Graham and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing 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

5 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
  4. Review
  5. 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

12 authors.

Zher Yin TanBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Joel K A AdadeBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Xiebin GuBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cody J S HechtBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Michael SalciusNovartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Bingqi TongBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Shuang LiuBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Seungmin HwangBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Frédéric J ZécriNovartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Daniel B GrahamBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Stuart L SchreiberBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Arena BioWorks, Cambridge, MA 02139, USA. Electronic address: stuart_schreiber@harvard.edu.
Ramnik J XavierBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

Funding

RP5: Chemical proteomic discovery of small-molecule probes for autophagy proteinsU19AI142784 · NIAID · UT SOUTHWESTERN MEDICAL CENTER · PI VIRGIN, HERBERT W · 2019 to 2023
$36.9M
Pilot & Feasibility ProgramP30DK043351 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI Ramnik J Xavier · 1991 to 2026
$35.3M
NIAID NIH HHS U19 AI142784NIDDK NIH HHS P30 DK043351
6 · The paper itself

Abstract

Chemical inducers of proximity (CIPs) are molecules that recruit one protein to another and introduce new functionalities toward modulating protein states and activities. While CIP-mediated recruitment of E3 ligases is widely exploited for the development of degraders, other therapeutic modalities remain underexplored. We describe a non-degrader CIP-DNA-encoded library (CIP-DEL) that recruits FKBP12 to target proteins using non-traditional acyclic structures, with an emphasis on introducing stereochemically diverse and rigid connectors to attach the combinatorial library. We deployed this strategy to modulate ATG16L1 T300A, which confers genetic susceptibility to Crohn's disease (CD), and identified a compound that stabilizes the variant protein against caspase-3 (Casp3) cleavage in a FKBP12-independent manner. We demonstrate in cellular models that this compound potentiates autophagy, and reverses the xenophagy defects as well as increased cytokine secretion characteristic of ATG16L1 T300A. This study provides a platform to access unexplored chemical space for CIP design to develop therapeutic modalities guided by human genetics.

Indexed as

AutophagyDNASmall Molecule LibrariesTacrolimus Binding Protein 1AAutophagy-Related ProteinsCaspase 3Crohn DiseaseHEK293 CellsHumansATG16L1 protein, humanAutophagy-Related ProteinsCaspase 3DNASmall Molecule LibrariesTacrolimus Binding Protein 1AATG16L1 T300Aautophagychemical inducers of proximityCrohn's DiseaseDNA-encoded libraryhuman genetic variant

Identifiers

PMID39753134
PMCPMC11928285

What Socratic holds

Textmetadata
LicenceTDM
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.