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. 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.