Lead Optimization of 2‑Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas

In glioblastoma multiforme (GBM), translocator protein (TSPO) and murine double minute (MDM)­2/p53 complex represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. H...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-05, Vol.59 (10), p.4526-4538
Main Authors: Daniele, Simona, La Pietra, Valeria, Barresi, Elisabetta, Di Maro, Salvatore, Da Pozzo, Eleonora, Robello, Marco, La Motta, Concettina, Cosconati, Sandro, Taliani, Sabrina, Marinelli, Luciana, Novellino, Ettore, Martini, Claudia, Da Settimo, Federico
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Proliferation - drug effects
Cell Survival - drug effects
Dipeptides - chemical synthesis
Dipeptides - chemistry
Dipeptides - pharmacology
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Glioblastoma - drug therapy
Glioblastoma - pathology
Humans
Models, Molecular
Molecular Structure
Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2 - metabolism
Receptors, GABA - metabolism
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary:In glioblastoma multiforme (GBM), translocator protein (TSPO) and murine double minute (MDM)­2/p53 complex represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. Herein, through a structure–activity relationship study, we developed derivatives 4–10 with improved potencies toward both TSPO and MDM2. As a result, compound 9: (i) reactivated the p53 functionality; (ii) inhibited the viability of two human GBM cells; (iii) impaired the proliferation of glioma cancer stem cells (CSCs), more resistant to chemotherapeutics and responsible of GBM recurrence; (iv) sensitized GBM cells and CSCs to the activity of temozolomide; (v) directed its effects preferentially toward tumor cells with respect to healthy ones. Thus, 9 may represent a promising cytotoxic agent, which is worthy of being further developed for a therapeutic approach against GBM, where the downstream p53 signaling is intact and TSPO is overexpressed.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b01767