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Development and Applications of Chimera Platforms for Tyrosine Phosphorylation

[Image: see text] Chimeric small molecules that induce post-translational modification (PTM) on a target protein by bringing it into proximity to a PTM-inducing enzyme are furnishing novel modalities to perturb protein function. Despite recent advances, such molecules are unavailable for a critical...

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Autores principales: Pergu, Rajaiah, Shoba, Veronika M., Chaudhary, Santosh K., Munkanatta Godage, Dhanushka N. P., Deb, Arghya, Singha, Santanu, Dhawa, Uttam, Singh, Prashant, Anokhina, Viktoriya, Singh, Sameek, Siriwardena, Sachini U., Choudhary, Amit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10450875/
https://www.ncbi.nlm.nih.gov/pubmed/37637727
http://dx.doi.org/10.1021/acscentsci.3c00200
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author Pergu, Rajaiah
Shoba, Veronika M.
Chaudhary, Santosh K.
Munkanatta Godage, Dhanushka N. P.
Deb, Arghya
Singha, Santanu
Dhawa, Uttam
Singh, Prashant
Anokhina, Viktoriya
Singh, Sameek
Siriwardena, Sachini U.
Choudhary, Amit
author_facet Pergu, Rajaiah
Shoba, Veronika M.
Chaudhary, Santosh K.
Munkanatta Godage, Dhanushka N. P.
Deb, Arghya
Singha, Santanu
Dhawa, Uttam
Singh, Prashant
Anokhina, Viktoriya
Singh, Sameek
Siriwardena, Sachini U.
Choudhary, Amit
author_sort Pergu, Rajaiah
collection PubMed
description [Image: see text] Chimeric small molecules that induce post-translational modification (PTM) on a target protein by bringing it into proximity to a PTM-inducing enzyme are furnishing novel modalities to perturb protein function. Despite recent advances, such molecules are unavailable for a critical PTM, tyrosine phosphorylation. Furthermore, the contemporary design paradigm of chimeric molecules, formed by joining a noninhibitory binder of the PTM-inducing enzyme with the binder of the target protein, prohibits the recruitment of most PTM-inducing enzymes as their noninhibitory binders are unavailable. Here, we report two platforms to generate phosphorylation-inducing chimeric small molecules (PHICS) for tyrosine phosphorylation. We generate PHICS from both noninhibitory binders (scantily available, platform 1) and kinase inhibitors (abundantly available, platform 2) using cysteine-based group transfer chemistry. PHICS triggered phosphorylation on tyrosine residues in diverse sequence contexts and target proteins (e.g., membrane-associated, cytosolic) and displayed multiple bioactivities, including the initiation of a growth receptor signaling cascade and the death of drug-resistant cancer cells. These studies provide an approach to induce biologically relevant PTM and lay the foundation for pharmacologic PTM editing (i.e., induction or removal) of target proteins using abundantly available inhibitors of PTM-inducing or -erasing enzymes.
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spelling pubmed-104508752023-08-26 Development and Applications of Chimera Platforms for Tyrosine Phosphorylation Pergu, Rajaiah Shoba, Veronika M. Chaudhary, Santosh K. Munkanatta Godage, Dhanushka N. P. Deb, Arghya Singha, Santanu Dhawa, Uttam Singh, Prashant Anokhina, Viktoriya Singh, Sameek Siriwardena, Sachini U. Choudhary, Amit ACS Cent Sci [Image: see text] Chimeric small molecules that induce post-translational modification (PTM) on a target protein by bringing it into proximity to a PTM-inducing enzyme are furnishing novel modalities to perturb protein function. Despite recent advances, such molecules are unavailable for a critical PTM, tyrosine phosphorylation. Furthermore, the contemporary design paradigm of chimeric molecules, formed by joining a noninhibitory binder of the PTM-inducing enzyme with the binder of the target protein, prohibits the recruitment of most PTM-inducing enzymes as their noninhibitory binders are unavailable. Here, we report two platforms to generate phosphorylation-inducing chimeric small molecules (PHICS) for tyrosine phosphorylation. We generate PHICS from both noninhibitory binders (scantily available, platform 1) and kinase inhibitors (abundantly available, platform 2) using cysteine-based group transfer chemistry. PHICS triggered phosphorylation on tyrosine residues in diverse sequence contexts and target proteins (e.g., membrane-associated, cytosolic) and displayed multiple bioactivities, including the initiation of a growth receptor signaling cascade and the death of drug-resistant cancer cells. These studies provide an approach to induce biologically relevant PTM and lay the foundation for pharmacologic PTM editing (i.e., induction or removal) of target proteins using abundantly available inhibitors of PTM-inducing or -erasing enzymes. American Chemical Society 2023-08-09 /pmc/articles/PMC10450875/ /pubmed/37637727 http://dx.doi.org/10.1021/acscentsci.3c00200 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Pergu, Rajaiah
Shoba, Veronika M.
Chaudhary, Santosh K.
Munkanatta Godage, Dhanushka N. P.
Deb, Arghya
Singha, Santanu
Dhawa, Uttam
Singh, Prashant
Anokhina, Viktoriya
Singh, Sameek
Siriwardena, Sachini U.
Choudhary, Amit
Development and Applications of Chimera Platforms for Tyrosine Phosphorylation
title Development and Applications of Chimera Platforms for Tyrosine Phosphorylation
title_full Development and Applications of Chimera Platforms for Tyrosine Phosphorylation
title_fullStr Development and Applications of Chimera Platforms for Tyrosine Phosphorylation
title_full_unstemmed Development and Applications of Chimera Platforms for Tyrosine Phosphorylation
title_short Development and Applications of Chimera Platforms for Tyrosine Phosphorylation
title_sort development and applications of chimera platforms for tyrosine phosphorylation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10450875/
https://www.ncbi.nlm.nih.gov/pubmed/37637727
http://dx.doi.org/10.1021/acscentsci.3c00200
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