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Identification of a new member of Mortaparib class of inhibitors that target mortalin and PARP1

Mortalin, a heat shock family protein enriched in cancer cells, is known to inactivate tumor suppressor protein p53. Abrogation of mortalin-p53 interaction and reactivation of p53 has been shown to trigger growth arrest/apoptosis in cancer cells and hence, suggested to be useful in cancer therapy. I...

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Autores principales: Meidinna, Hazna Noor, Shefrin, Seyad, Sari, Anissa Nofita, Zhang, Huayue, Dhanjal, Jaspreet Kaur, Kaul, Sunil C., Sundar, Durai, Wadhwa, Renu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9510692/
https://www.ncbi.nlm.nih.gov/pubmed/36172283
http://dx.doi.org/10.3389/fcell.2022.918970
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author Meidinna, Hazna Noor
Shefrin, Seyad
Sari, Anissa Nofita
Zhang, Huayue
Dhanjal, Jaspreet Kaur
Kaul, Sunil C.
Sundar, Durai
Wadhwa, Renu
author_facet Meidinna, Hazna Noor
Shefrin, Seyad
Sari, Anissa Nofita
Zhang, Huayue
Dhanjal, Jaspreet Kaur
Kaul, Sunil C.
Sundar, Durai
Wadhwa, Renu
author_sort Meidinna, Hazna Noor
collection PubMed
description Mortalin, a heat shock family protein enriched in cancer cells, is known to inactivate tumor suppressor protein p53. Abrogation of mortalin-p53 interaction and reactivation of p53 has been shown to trigger growth arrest/apoptosis in cancer cells and hence, suggested to be useful in cancer therapy. In this premise, we earlier screened a chemical library to identify potential disruptors of mortalin-p53 interaction, and reported two novel synthetic small molecules (5-[1-(4-methoxyphenyl) (1,2,3,4-tetraazol-5-yl)]-4-phenylpyrimidine-2-ylamine) and (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole) called Mortaparib and Mortaparib(Plus), respectively. These compounds were shown to possess anticancer activity that was mediated through targeting mortalin and PARP1 proteins, essential for cancer cell survival and proliferation. Here, we report characterization of the third compound, {4-[(4-amino-5-thiophen-2-yl-1,2,4-triazol-3-yl)sulfanylmethyl]-N-(4-methoxyphenyl)-1,3-thiazol-2-amine}, isolated in the same screening. Extensive computational and molecular analyses suggested that the new compound has the capability to interact with mortalin, p53, and PARP1. We provide evidence that this new compound, although required in high concentration as compared to the earlier two compounds (Mortaparib and Mortaparib(Plus)) and hence called Mortaparib(Mild), also downregulates mortalin and PARP1 expression and functions in multiple ways impeding cancer cell proliferation and migration characteristics. Mortaparib(Mild) is a novel candidate anticancer compound that warrants further experimental and clinical attention.
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spelling pubmed-95106922022-09-27 Identification of a new member of Mortaparib class of inhibitors that target mortalin and PARP1 Meidinna, Hazna Noor Shefrin, Seyad Sari, Anissa Nofita Zhang, Huayue Dhanjal, Jaspreet Kaur Kaul, Sunil C. Sundar, Durai Wadhwa, Renu Front Cell Dev Biol Cell and Developmental Biology Mortalin, a heat shock family protein enriched in cancer cells, is known to inactivate tumor suppressor protein p53. Abrogation of mortalin-p53 interaction and reactivation of p53 has been shown to trigger growth arrest/apoptosis in cancer cells and hence, suggested to be useful in cancer therapy. In this premise, we earlier screened a chemical library to identify potential disruptors of mortalin-p53 interaction, and reported two novel synthetic small molecules (5-[1-(4-methoxyphenyl) (1,2,3,4-tetraazol-5-yl)]-4-phenylpyrimidine-2-ylamine) and (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole) called Mortaparib and Mortaparib(Plus), respectively. These compounds were shown to possess anticancer activity that was mediated through targeting mortalin and PARP1 proteins, essential for cancer cell survival and proliferation. Here, we report characterization of the third compound, {4-[(4-amino-5-thiophen-2-yl-1,2,4-triazol-3-yl)sulfanylmethyl]-N-(4-methoxyphenyl)-1,3-thiazol-2-amine}, isolated in the same screening. Extensive computational and molecular analyses suggested that the new compound has the capability to interact with mortalin, p53, and PARP1. We provide evidence that this new compound, although required in high concentration as compared to the earlier two compounds (Mortaparib and Mortaparib(Plus)) and hence called Mortaparib(Mild), also downregulates mortalin and PARP1 expression and functions in multiple ways impeding cancer cell proliferation and migration characteristics. Mortaparib(Mild) is a novel candidate anticancer compound that warrants further experimental and clinical attention. Frontiers Media S.A. 2022-09-12 /pmc/articles/PMC9510692/ /pubmed/36172283 http://dx.doi.org/10.3389/fcell.2022.918970 Text en Copyright © 2022 Meidinna, Shefrin, Sari, Zhang, Dhanjal, Kaul, Sundar and Wadhwa. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Meidinna, Hazna Noor
Shefrin, Seyad
Sari, Anissa Nofita
Zhang, Huayue
Dhanjal, Jaspreet Kaur
Kaul, Sunil C.
Sundar, Durai
Wadhwa, Renu
Identification of a new member of Mortaparib class of inhibitors that target mortalin and PARP1
title Identification of a new member of Mortaparib class of inhibitors that target mortalin and PARP1
title_full Identification of a new member of Mortaparib class of inhibitors that target mortalin and PARP1
title_fullStr Identification of a new member of Mortaparib class of inhibitors that target mortalin and PARP1
title_full_unstemmed Identification of a new member of Mortaparib class of inhibitors that target mortalin and PARP1
title_short Identification of a new member of Mortaparib class of inhibitors that target mortalin and PARP1
title_sort identification of a new member of mortaparib class of inhibitors that target mortalin and parp1
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9510692/
https://www.ncbi.nlm.nih.gov/pubmed/36172283
http://dx.doi.org/10.3389/fcell.2022.918970
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