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Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C

[Image: see text] The tumor suppressor protein p53 is inactivated in the majority of human cancers and remains a prime target for developing new drugs to reactivate its tumor suppressing activity for anticancer therapies. The oncogenic p53 mutant Y220C accounts for approximately 125,000 new cancer c...

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Autores principales: Stephenson Clarke, Joseph R., Douglas, Leon R., Duriez, Patrick J., Balourdas, Dimitrios-Ilias, Joerger, Andreas C., Khadiullina, Raniya, Bulatov, Emil, Baud, Matthias G. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9667543/
https://www.ncbi.nlm.nih.gov/pubmed/36407959
http://dx.doi.org/10.1021/acsptsci.2c00164
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author Stephenson Clarke, Joseph R.
Douglas, Leon R.
Duriez, Patrick J.
Balourdas, Dimitrios-Ilias
Joerger, Andreas C.
Khadiullina, Raniya
Bulatov, Emil
Baud, Matthias G. J.
author_facet Stephenson Clarke, Joseph R.
Douglas, Leon R.
Duriez, Patrick J.
Balourdas, Dimitrios-Ilias
Joerger, Andreas C.
Khadiullina, Raniya
Bulatov, Emil
Baud, Matthias G. J.
author_sort Stephenson Clarke, Joseph R.
collection PubMed
description [Image: see text] The tumor suppressor protein p53 is inactivated in the majority of human cancers and remains a prime target for developing new drugs to reactivate its tumor suppressing activity for anticancer therapies. The oncogenic p53 mutant Y220C accounts for approximately 125,000 new cancer cases per annum and is one of the most prevalent p53 mutants overall. It harbors a narrow, mutationally induced pocket at the surface of the DNA-binding domain that destabilizes p53, leading to its rapid denaturation and aggregation. Here, we present the structure-guided development of high-affinity small molecules stabilizing p53-Y220C in vitro, along with the synthetic routes developed in the process, in vitro structure–activity relationship data, and confirmation of their binding mode by protein X-ray crystallography. We disclose two new chemical probes displaying sub-micromolar binding affinity in vitro, marking an important milestone since the discovery of the first small-molecule ligand of Y220C in 2008. New chemical probe JC744 displayed a K(d) = 320 nM, along with potent in vitro protein stabilization. This study, therefore, represents a significant advance toward high-affinity Y220C ligands for clinical evaluation.
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spelling pubmed-96675432023-10-11 Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C Stephenson Clarke, Joseph R. Douglas, Leon R. Duriez, Patrick J. Balourdas, Dimitrios-Ilias Joerger, Andreas C. Khadiullina, Raniya Bulatov, Emil Baud, Matthias G. J. ACS Pharmacol Transl Sci [Image: see text] The tumor suppressor protein p53 is inactivated in the majority of human cancers and remains a prime target for developing new drugs to reactivate its tumor suppressing activity for anticancer therapies. The oncogenic p53 mutant Y220C accounts for approximately 125,000 new cancer cases per annum and is one of the most prevalent p53 mutants overall. It harbors a narrow, mutationally induced pocket at the surface of the DNA-binding domain that destabilizes p53, leading to its rapid denaturation and aggregation. Here, we present the structure-guided development of high-affinity small molecules stabilizing p53-Y220C in vitro, along with the synthetic routes developed in the process, in vitro structure–activity relationship data, and confirmation of their binding mode by protein X-ray crystallography. We disclose two new chemical probes displaying sub-micromolar binding affinity in vitro, marking an important milestone since the discovery of the first small-molecule ligand of Y220C in 2008. New chemical probe JC744 displayed a K(d) = 320 nM, along with potent in vitro protein stabilization. This study, therefore, represents a significant advance toward high-affinity Y220C ligands for clinical evaluation. American Chemical Society 2022-10-11 /pmc/articles/PMC9667543/ /pubmed/36407959 http://dx.doi.org/10.1021/acsptsci.2c00164 Text en © 2022 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 Stephenson Clarke, Joseph R.
Douglas, Leon R.
Duriez, Patrick J.
Balourdas, Dimitrios-Ilias
Joerger, Andreas C.
Khadiullina, Raniya
Bulatov, Emil
Baud, Matthias G. J.
Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C
title Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C
title_full Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C
title_fullStr Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C
title_full_unstemmed Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C
title_short Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C
title_sort discovery of nanomolar-affinity pharmacological chaperones stabilizing the oncogenic p53 mutant y220c
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9667543/
https://www.ncbi.nlm.nih.gov/pubmed/36407959
http://dx.doi.org/10.1021/acsptsci.2c00164
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