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

ABSTRACT: 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.

SUBMITTER: Meidinna HN

PROVIDER: S-EPMC9510692 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Meidinna Hazna Noor HN Shefrin Seyad S Sari Anissa Nofita AN Zhang Huayue H Dhanjal Jaspreet Kaur JK Kaul Sunil C SC Sundar Durai D Wadhwa Renu R

Frontiers in cell and developmental biology 20220912

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-t ...[more]

PMID: 36172283

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Project description:BackgroundMortalin is enriched in a large variety of cancers and has been shown to contribute to proliferation and migration of cancer cells in multiple ways. It has been shown to bind to p53 protein in cell cytoplasm and nucleus causing inactivation of its tumor suppressor activity in cancer cells. Several other activities of mortalin including mitochondrial biogenesis, ATP production, chaperoning, anti-apoptosis contribute to pro-proliferative and migration characteristics of cancer cells. Mortalin-compromised cancer cells have been shown to undergo apoptosis in in vitro and in vivo implying that it could be a potential target for cancer therapy.MethodsWe implemented a screening of a chemical library for compounds with potential to abrogate cancer cell specific mortalin-p53 interactions, and identified a new compound (named it as Mortaparib) that caused nuclear enrichment of p53 and shift in mortalin from perinuclear (typical of cancer cells) to pancytoplasmic (typical of normal cells). Biochemical and molecular assays were used to demonstrate the effect of Mortaparib on mortalin, p53 and PARP1 activities.ResultsMolecular homology search revealed that Mortaparib is a novel compound that showed strong cytotoxicity to ovarian, cervical and breast cancer cells. Bioinformatics analysis revealed that although Mortaparib could interact with mortalin, its binding with p53 interaction site was not stable. Instead, it caused transcriptional repression of mortalin leading to activation of p53 and growth arrest/apoptosis of cancer cells. By extensive computational and experimental analyses, we demonstrate that Mortaparib is a dual inhibitor of mortalin and PARP1. It targets mortalin, PARP1 and mortalin-PARP1 interactions leading to inactivation of PARP1 that triggers growth arrest/apoptosis signaling. Consistent with the role of mortalin and PARP1 in cancer cell migration, metastasis and angiogenesis, Mortaparib-treated cells showed inhibition of these phenotypes. In vivo tumor suppression assays showed that Mortaparib is a potent tumor suppressor small molecule and awaits clinical trials.ConclusionThese findings report (i) the discovery of Mortaparib as a first dual inhibitor of mortalin and PARP1 (both frequently enriched in cancers), (ii) its molecular mechanism of action, and (iii) in vitro and in vivo tumor suppressor activity that emphasize its potential as an anticancer drug.

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

Publications

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

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