Cargando…

OligoTRAFTACs: A generalizable method for transcription factor degradation

Dysregulated transcription factors (TFs) that rewire gene expression circuitry are frequently identified as key players in disease. Although several TFs have been drugged with small molecules, the majority of oncogenic TFs are not currently pharmaceutically tractable due to their paucity of ligandab...

Descripción completa

Detalles Bibliográficos
Autores principales: Samarasinghe, Kusal T. G., An, Elvira, Genuth, Miriam A., Chu, Ling, Holley, Scott A., Crews, Craig M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: RSC 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9428672/
https://www.ncbi.nlm.nih.gov/pubmed/36128504
http://dx.doi.org/10.1039/d2cb00138a
_version_ 1784779171095904256
author Samarasinghe, Kusal T. G.
An, Elvira
Genuth, Miriam A.
Chu, Ling
Holley, Scott A.
Crews, Craig M.
author_facet Samarasinghe, Kusal T. G.
An, Elvira
Genuth, Miriam A.
Chu, Ling
Holley, Scott A.
Crews, Craig M.
author_sort Samarasinghe, Kusal T. G.
collection PubMed
description Dysregulated transcription factors (TFs) that rewire gene expression circuitry are frequently identified as key players in disease. Although several TFs have been drugged with small molecules, the majority of oncogenic TFs are not currently pharmaceutically tractable due to their paucity of ligandable pockets. The first generation of transcription factor targeting chimeras (TRAFTACs) was developed to target TFs for proteasomal degradation by exploiting their DNA binding ability. In the current study, we have developed the second generation TRAFTACs (“oligoTRAFTACs”) composed of a TF-binding oligonucleotide and an E3 ligase-recruiting ligand. Herein, we demonstrate the development of oligoTRAFTACs to induce the degradation of two oncogenic TFs, c-Myc and brachyury. In addition, we show that brachyury can be successfully degraded by oligoTRAFTACs in chordoma cell lines. Furthermore, zebrafish experiments demonstrate in vivo oligoTRAFTAC activity. Overall, our data demonstrate oligoTRAFTACs as a generalizable platform towards difficult-to-drug TFs and their degradability via the proteasomal pathway.
format Online
Article
Text
id pubmed-9428672
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher RSC
record_format MEDLINE/PubMed
spelling pubmed-94286722022-09-19 OligoTRAFTACs: A generalizable method for transcription factor degradation Samarasinghe, Kusal T. G. An, Elvira Genuth, Miriam A. Chu, Ling Holley, Scott A. Crews, Craig M. RSC Chem Biol Chemistry Dysregulated transcription factors (TFs) that rewire gene expression circuitry are frequently identified as key players in disease. Although several TFs have been drugged with small molecules, the majority of oncogenic TFs are not currently pharmaceutically tractable due to their paucity of ligandable pockets. The first generation of transcription factor targeting chimeras (TRAFTACs) was developed to target TFs for proteasomal degradation by exploiting their DNA binding ability. In the current study, we have developed the second generation TRAFTACs (“oligoTRAFTACs”) composed of a TF-binding oligonucleotide and an E3 ligase-recruiting ligand. Herein, we demonstrate the development of oligoTRAFTACs to induce the degradation of two oncogenic TFs, c-Myc and brachyury. In addition, we show that brachyury can be successfully degraded by oligoTRAFTACs in chordoma cell lines. Furthermore, zebrafish experiments demonstrate in vivo oligoTRAFTAC activity. Overall, our data demonstrate oligoTRAFTACs as a generalizable platform towards difficult-to-drug TFs and their degradability via the proteasomal pathway. RSC 2022-07-26 /pmc/articles/PMC9428672/ /pubmed/36128504 http://dx.doi.org/10.1039/d2cb00138a Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Samarasinghe, Kusal T. G.
An, Elvira
Genuth, Miriam A.
Chu, Ling
Holley, Scott A.
Crews, Craig M.
OligoTRAFTACs: A generalizable method for transcription factor degradation
title OligoTRAFTACs: A generalizable method for transcription factor degradation
title_full OligoTRAFTACs: A generalizable method for transcription factor degradation
title_fullStr OligoTRAFTACs: A generalizable method for transcription factor degradation
title_full_unstemmed OligoTRAFTACs: A generalizable method for transcription factor degradation
title_short OligoTRAFTACs: A generalizable method for transcription factor degradation
title_sort oligotraftacs: a generalizable method for transcription factor degradation
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9428672/
https://www.ncbi.nlm.nih.gov/pubmed/36128504
http://dx.doi.org/10.1039/d2cb00138a
work_keys_str_mv AT samarasinghekusaltg oligotraftacsageneralizablemethodfortranscriptionfactordegradation
AT anelvira oligotraftacsageneralizablemethodfortranscriptionfactordegradation
AT genuthmiriama oligotraftacsageneralizablemethodfortranscriptionfactordegradation
AT chuling oligotraftacsageneralizablemethodfortranscriptionfactordegradation
AT holleyscotta oligotraftacsageneralizablemethodfortranscriptionfactordegradation
AT crewscraigm oligotraftacsageneralizablemethodfortranscriptionfactordegradation