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Targeting oncoproteins with a positive selection assay for protein degraders

Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. For example, thalidomide-like drugs (IMiDs) degrade the critical multip...

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Autores principales: Koduri, Vidyasagar, Duplaquet, Leslie, Lampson, Benjamin L., Wang, Adam C., Sabet, Amin H., Ishoey, Mette, Paulk, Joshiawa, Teng, Mingxing, Harris, Isaac S., Endress, Jennifer E., Liu, Xiaoxi, Dasilva, Ethan, Paulo, Joao A., Briggs, Kimberly J., Doench, John G., Ott, Christopher J., Zhang, Tinghu, Donovan, Katherine A., Fischer, Eric S., Gygi, Steven P., Gray, Nathanael S., Bradner, James, Medin, Jeffrey A., Buhrlage, Sara J., Oser, Matthew G., Kaelin, William G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864573/
https://www.ncbi.nlm.nih.gov/pubmed/33547076
http://dx.doi.org/10.1126/sciadv.abd6263
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author Koduri, Vidyasagar
Duplaquet, Leslie
Lampson, Benjamin L.
Wang, Adam C.
Sabet, Amin H.
Ishoey, Mette
Paulk, Joshiawa
Teng, Mingxing
Harris, Isaac S.
Endress, Jennifer E.
Liu, Xiaoxi
Dasilva, Ethan
Paulo, Joao A.
Briggs, Kimberly J.
Doench, John G.
Ott, Christopher J.
Zhang, Tinghu
Donovan, Katherine A.
Fischer, Eric S.
Gygi, Steven P.
Gray, Nathanael S.
Bradner, James
Medin, Jeffrey A.
Buhrlage, Sara J.
Oser, Matthew G.
Kaelin, William G.
author_facet Koduri, Vidyasagar
Duplaquet, Leslie
Lampson, Benjamin L.
Wang, Adam C.
Sabet, Amin H.
Ishoey, Mette
Paulk, Joshiawa
Teng, Mingxing
Harris, Isaac S.
Endress, Jennifer E.
Liu, Xiaoxi
Dasilva, Ethan
Paulo, Joao A.
Briggs, Kimberly J.
Doench, John G.
Ott, Christopher J.
Zhang, Tinghu
Donovan, Katherine A.
Fischer, Eric S.
Gygi, Steven P.
Gray, Nathanael S.
Bradner, James
Medin, Jeffrey A.
Buhrlage, Sara J.
Oser, Matthew G.
Kaelin, William G.
author_sort Koduri, Vidyasagar
collection PubMed
description Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcription factors IKZF1 and IKZF3 by recruiting them to the cereblon E3 ubiquitin ligase. Current loss of signal (“down”) assays for identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic ranges, and false positives from compounds that nonspecifically suppress transcription or translation. Here, we describe a gain of signal (“up”) assay for degraders. In arrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner. In a pooled CRISPR-Cas9–based screen, we found that CDK2 regulates the abundance of the ASCL1 oncogenic transcription factor. This methodology should facilitate the identification of drugs that directly or indirectly degrade undruggable proteins.
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spelling pubmed-78645732021-02-16 Targeting oncoproteins with a positive selection assay for protein degraders Koduri, Vidyasagar Duplaquet, Leslie Lampson, Benjamin L. Wang, Adam C. Sabet, Amin H. Ishoey, Mette Paulk, Joshiawa Teng, Mingxing Harris, Isaac S. Endress, Jennifer E. Liu, Xiaoxi Dasilva, Ethan Paulo, Joao A. Briggs, Kimberly J. Doench, John G. Ott, Christopher J. Zhang, Tinghu Donovan, Katherine A. Fischer, Eric S. Gygi, Steven P. Gray, Nathanael S. Bradner, James Medin, Jeffrey A. Buhrlage, Sara J. Oser, Matthew G. Kaelin, William G. Sci Adv Research Articles Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcription factors IKZF1 and IKZF3 by recruiting them to the cereblon E3 ubiquitin ligase. Current loss of signal (“down”) assays for identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic ranges, and false positives from compounds that nonspecifically suppress transcription or translation. Here, we describe a gain of signal (“up”) assay for degraders. In arrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner. In a pooled CRISPR-Cas9–based screen, we found that CDK2 regulates the abundance of the ASCL1 oncogenic transcription factor. This methodology should facilitate the identification of drugs that directly or indirectly degrade undruggable proteins. American Association for the Advancement of Science 2021-02-05 /pmc/articles/PMC7864573/ /pubmed/33547076 http://dx.doi.org/10.1126/sciadv.abd6263 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Koduri, Vidyasagar
Duplaquet, Leslie
Lampson, Benjamin L.
Wang, Adam C.
Sabet, Amin H.
Ishoey, Mette
Paulk, Joshiawa
Teng, Mingxing
Harris, Isaac S.
Endress, Jennifer E.
Liu, Xiaoxi
Dasilva, Ethan
Paulo, Joao A.
Briggs, Kimberly J.
Doench, John G.
Ott, Christopher J.
Zhang, Tinghu
Donovan, Katherine A.
Fischer, Eric S.
Gygi, Steven P.
Gray, Nathanael S.
Bradner, James
Medin, Jeffrey A.
Buhrlage, Sara J.
Oser, Matthew G.
Kaelin, William G.
Targeting oncoproteins with a positive selection assay for protein degraders
title Targeting oncoproteins with a positive selection assay for protein degraders
title_full Targeting oncoproteins with a positive selection assay for protein degraders
title_fullStr Targeting oncoproteins with a positive selection assay for protein degraders
title_full_unstemmed Targeting oncoproteins with a positive selection assay for protein degraders
title_short Targeting oncoproteins with a positive selection assay for protein degraders
title_sort targeting oncoproteins with a positive selection assay for protein degraders
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864573/
https://www.ncbi.nlm.nih.gov/pubmed/33547076
http://dx.doi.org/10.1126/sciadv.abd6263
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