Identification and Characterization of MortaparibPlus—A Novel Triazole Derivative That Targets Mortalin-p53 Interaction and Inhibits Cancer-Cell Proliferation by Wild-Type p53-Dependent and -Independent Mechanisms

Anissa Nofita Sari, Ahmed Elwakeel, Jaspreet Kaur Dhanjal, Vipul Kumar, Durai Sundar, Sunil C. Kaul, Renu Wadhwa

    Research output: Contribution to journalArticlepeer-review

    9 Citations (Scopus)
    11 Downloads (Pure)

    Abstract

    p53 has an essential role in suppressing the carcinogenesis process by inducing cell cycle arrest/apoptosis/senescence. Mortalin/GRP75 is a member of the Hsp70 protein family that binds to p53 causing its sequestration in the cell cytoplasm. Hence, p53 cannot translocate to the nucleus to execute its canonical tumour suppression function as a transcription factor. Abrogation of mortalin-p53 interaction and subsequent reactivation of p53’s tumour suppression function has been anticipated as a possible approach in developing a novel cancer therapeutic drug candidate. A chemical library was screened in a high-content screening system to identify potential mortalin-p53 interaction disruptors. By four rounds of visual assays for mortalin and p53, we identified a novel synthetic small-molecule triazole derivative (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole, henceforth named MortaparibPlus). Its activities were validated using multiple bioinformatics and experimental approaches in colorectal cancer cells possessing either wild-type (HCT116) or mutant (DLD-1) p53. Bioinformatics and computational analyses predicted the ability of MortaparibPlus to competitively prevent the interaction of mortalin with p53 as it interacted with the p53 binding site of mortalin. Immunoprecipitation analyses demonstrated the abrogation of mortalin-p53 complex formation in MortaparibPlus-treated cells that showed growth arrest and apoptosis mediated by activation of p21WAF1, or BAX and PUMA signalling, respectively. Furthermore, we demonstrate that MortaparibPlus-induced cytotoxicity to cancer cells is mediated by multiple mechanisms that included the inhibition of PARP1, up-regulation of p73, and also the down-regulation of mortalin and CARF proteins that play critical roles in carcinogenesis. MortaparibPlus is a novel multimodal candidate anticancer drug that warrants further experimental and clinical attention. View Full-Text
    Original languageEnglish
    Article number835
    Number of pages25
    JournalCancers
    Volume13
    Issue number4
    DOIs
    Publication statusPublished - 17 Feb 2021

    Bibliographical note

    Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    This article is an open access article distributed under the terms and
    conditions of the Creative Commons Attribution (CC BY) license
    (https://creativecommons.org/licenses/by/4.0/).

    Keywords

    • potential anticancer drug
    • Inhibition
    • PARP1
    • novel small-molecule triazole derivative
    • mortalin-p53 interaction
    • Cancer

    Fingerprint

    Dive into the research topics of 'Identification and Characterization of MortaparibPlus—A Novel Triazole Derivative That Targets Mortalin-p53 Interaction and Inhibits Cancer-Cell Proliferation by Wild-Type p53-Dependent and -Independent Mechanisms'. Together they form a unique fingerprint.

    Cite this