A Novel Small Molecule p53 Stabilizer for Brain Cell Differentiation

Abstract

Brain tumor, as any type of cancer, is assumed to be sustained by a small subpopulation of stem-like cells with distinctive properties that allow them to survive conventional therapies and drive tumor recurrence. Thus, the identification of new molecules capable of controlling stemness properties may be key in developing effective therapeutic strategies for cancer by inducing stem-like cells differentiation. Spiropyrazoline oxindoles have previously been shown to induce apoptosis and cell cycle arrest, as well as upregulate p53 steady-state levels, while decreasing its main inhibitor MDM2 in the HCT116 human colorectal carcinoma cell line. In this study, we made modifications in this scaffold by including combinations of different substituents in the pyrazoline ring in order to obtain novel small molecules that could modulate p53 activity and act as differentiation inducer agents. The antiproliferative activity of the synthesized compounds was assessed using the isogenic pair of HCT116 cell lines differing in the presence or absence of the p53 gene. Among the tested spirooxindoles, spiropyrazoline oxindole 1a was selective against the cancer cell line expressing wild-type p53 and presented low cytotoxicity. This small molecule induced neural stem cell (NSC) differentiation through reduced SOX2 (marker of multipotency) and increased βIII-tubulin (marker of neural differentiation) which suggests a great potential as a non-toxic inducer of cell differentiation. More importantly, in glioma cancer cells (GL-261), compound 1a reduced stemness, by decreasing SOX2 protein levels, while also promoting chemotherapy sensitization. These results highlight the potential of p53 modulators for brain cell differentiation, with spirooxindole 1a representing a promising lead molecule for the development of new brain antitumor drugs.

MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy

“…The modified compound spiropyrazoline oxindole 1a was tested on the glioma cell line GL-261, alone and in combination with TMZ. These studies revealed an effective reduction in stemness through the reduction of the SOX2 protein levels, thereby promoting chemotherapy sensitization (149). Other spirooxindoles entered clinical trials and have been or are being studied in patients with advanced solid tumors and AML (MI77301(SAR405838), DS-3032b/milademetan, APG-115) (27,54).…”

“…The synergism of combining MDM2 inhibition with chemotherapeutics has shown to be effective in AML and multiple trials are running in diverse tumor types (NCT04190550, NCT03725436, NCT03031730, NCT04113616, NCT04275518) (54). In GB, multiple pre-clinical studies have already proven that MDM2 inhibition induces chemosensitization, including Nutlin-3a, RG7112, spiropyrazoline oxindole 1a, RITA, SP-141 and SGT-53 therapy (146,149,159,160,174,217,221). Nutlin-3a enhanced antitumor activity of TMZ in a humanized intracranial patient-derived xenograft model of GB (222).…”

Recent Synthetic Approaches towards Small Molecule Reactivators of p53

“…The pink color in the structures highlights the side chain of the bioisosteric replacements of the 6chlorooxindole group in RO8994. Later in 2015, Ivanenkov's group reported the regioselective synthesis of a series of compounds containing the spiro-indolinone scaffold from the one-pot reaction of commercially available 2thioxoimidazol-4-one 89, sarcosine 90 and isatin 91 (Scheme 22)[132]. Such molecules were evaluated on their ability induce apoptosis and block the proliferation of HepG2, Hek293, MCF-7, SiHa and HCT116 cell lines.…”