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

  • J Med Chem. 2016 May 26;59(10):4526-38. doi: 10.1021/acs.jmedchem.5b01767.
Simona Daniele  1 ,  Valeria La Pietra  2 ,  Elisabetta Barresi  1 ,  Salvatore Di Maro  3 ,  Eleonora Da Pozzo  1 ,  Marco Robello  1 ,  Concettina La Motta  1 ,  Sandro Cosconati  3 ,  Sabrina Taliani  1 ,  Luciana Marinelli  2 ,  Ettore Novellino  2 ,  Claudia Martini  1 ,  Federico Da Settimo  1
Affiliations
  • 1. Department of Pharmacy, University of Pisa , Pisa 56126, Italy.
  • 2. Department of Pharmacy, University of Naples Federico II , Via Montesano 49, Naples 80131, Italy.
  • 3. DiSTABiF, Seconda Università di Napoli , Caserta 81100, Italy.
PMID: 27050782 DOI: 10.1021/acs.jmedchem.5b01767
Abstract

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.

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