Format

Send to

Choose Destination
ACS Cent Sci. 2019 Jun 26;5(6):1079-1084. doi: 10.1021/acscentsci.9b00224. Epub 2019 May 9.

Targeted Protein Internalization and Degradation by ENDosome TArgeting Chimeras (ENDTACs).

Author information

1
Department of Molecular, Cellular and Developmental Biology, Yale University, 219 Prospect Street, New Haven, Connecticut 06511, United States.
2
Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States.
3
Department of Pharmacology, Yale University, New Haven, Connecticut 06511, United States.

Abstract

Targeted protein degradation has generated excitement in chemical biology and drug discovery throughout academia and industry. By hijacking the machinery responsible for protein degradation via the ubiquitin proteasome system (UPS), various cellular targets have been selectively degraded. However, since the tools used, often termed PROteolysis TArgeting Chimeras (PROTACs), hijack the intracellular quality control machinery, this technology can only access targets within the cell. Extracellular targets such as growth factors, cytokines, and chemokines bind to cell surface receptors, often initiating aberrant signaling in multiple diseases such as cancer and inflammation. However, efforts to develop small molecule inhibitors for these extracellular target proteins have been challenging. Herein, we developed a proof-of-concept approach to evaluate if extracellular proteins can be internalized and degraded via the receptor-mediated endolysosomal pathway. Using a heterodimeric molecule, termed "ENDosome TArgeting Chimera" (ENDTAC), internalization and degradation of an extracellular recombinant eGFP-HT7 fusion protein was achieved by hijacking the decoy GPCR receptor, CXCR7. This proof-of-concept study suggests that using ENDTACs to co-opt the endosomal-lysosomal degradation pathway, in contrast to PROTACs using the UPS, may provide an avenue for degrading extracellular targets such as cytokines. Overall, the technology described herein provides a novel expansion to the field of targeted protein degradation.

Conflict of interest statement

The authors declare the following competing financial interest(s): C.M.C. is a consultant to and shareholder in Arvinas, which partially supports research in his lab.

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center