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

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

  • Cell Chem Biol. 2024 Dec 30:S2451-9456(24)00491-4. doi: 10.1016/j.chembiol.2024.12.002.
Zher Yin Tan 1,  Joel K A Adade 2,  Xiebin Gu 2,  Cody J S Hecht 2,  Michael Salcius 3,  Bingqi Tong 2,  Shuang Liu 2,  Seungmin Hwang 2,  Frédéric J Zécri 3,  Daniel B Graham 4,  Stuart L Schreiber 5,  Ramnik J Xavier 6
Affiliations

Affiliations

  • 1 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
  • 2 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 3 Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
  • 4 Broad 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.
  • 5 Broad 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.
  • 6 Broad 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.
PMID: 39753134 DOI: 10.1016/j.chembiol.2024.12.002
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.

Keywords

ATG16L1 T300A; Crohn's Disease; DNA-encoded library; autophagy; chemical inducers of proximity; human genetic variant.

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