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

doi:10.3390/cancers13040835

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

Cancers (Basel). 2021 Feb 17;13(4):835. doi: 10.3390/cancers13040835.

Authors

Anissa Nofita Sari^{1

2}, Ahmed Elwakeel^{1

2}, Jaspreet Kaur Dhanjal¹, Vipul Kumar³, Durai Sundar³, Sunil C Kaul¹, Renu Wadhwa^{1

2}

Affiliations

¹ AIST-INDIA DAILAB, National Institute of Advanced Industrial Science & Technology (AIST), Central 5-41, Tsukuba 305-8565, Japan.
² School of Integrative & Global Majors (SIGMA), University of Tsukuba, Tsukuba 305-8577, Japan.
³ DAILAB, Department of Biochemical Engineering & Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110-016, India.

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 Mortaparib^Plus). 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 Mortaparib^Plus 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 Mortaparib^Plus-treated cells that showed growth arrest and apoptosis mediated by activation of p21^WAF1, or BAX and PUMA signalling, respectively. Furthermore, we demonstrate that Mortaparib^Plus-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. Mortaparib^Plus is a novel multimodal candidate anticancer drug that warrants further experimental and clinical attention.

Keywords: PARP1; cancer; inhibition; mortalin-p53 interaction; novel small-molecule triazole derivative; potential anticancer drug.