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 MortaparibPlus, 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 MortaparibPlus) and hence called MortaparibMild, also downregulates mortalin and PARP1 expression and functions in multiple ways impeding cancer cell proliferation and migration characteristics. MortaparibMild is a novel candidate anticancer compound that warrants further experimental and clinical attention.

Synthetic Small Molecule Modulators of Hsp70 and Hsp40 Chaperones as Promising Anticancer Agents

“…In contrast to colon cancer cells, in breast cancer cells, compound 24b upregulated only p21 in the p53-wildtype MCF-7 cells, while T47D cells (p53 L194F ) treated with compound 24b showed no p21 changes but activation of PARP1, albeit compound 24b inhibited the mortalin-p53 interaction in both cell lines [ 101 ]. More recently, compound 24c ( Figure 4 , mortaparib mild ) was identified as an inhibitor of PARP1 and mortalin-p53 interaction in HCT-116 cells, however, at higher concentrations than compounds 24a and 24c , thus leading to the attribute “mild” for compound 24c [ 102 ].…”