TY - JOUR
T1 - Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme
AU - Sestito, Simona
AU - Nesi, Giulia
AU - Daniele, Simona
AU - Martelli, Alma
AU - Digiacomo, Maria
AU - Borghini, Alice
AU - Pietra, Daniele
AU - Calderone, Vincenzo
AU - Lapucci, Annalina
AU - Falasca, Marco
AU - Parrella, Paola
AU - Notarangelo, Angelantonio
AU - Breschi, Maria C.
AU - Macchia, Marco
AU - Martini, Claudia
AU - Rapposelli, Simona
PY - 2015/11/13
Y1 - 2015/11/13
N2 - Aggressive behavior and diffuse infiltrative growth are the main features of Glioblastoma multiforme (GBM), together with the high degree of resistance and recurrence. Evidence indicate that GBM-derived stem cells (GSCs), endowed with unlimited proliferative potential, play a critical role in tumor development and maintenance. Among the many signaling pathways involved in maintaining GSC stemness, tumorigenic potential, and anti-apoptotic properties, the PDK1/Akt pathway is a challenging target to develop new potential agents able to affect GBM resistance to chemotherapy. In an effort to find new PDK1/Akt inhibitors, we rationally designed and synthesized a small family of 2-oxindole derivatives. Among them, compound 3 inhibited PDK1 kinase and downstream effectors such as CHK1, GS3Kα and GS3Kβ, which contribute to GCS survival. Compound 3 appeared to be a good tool for studying the role of the PDK1/Akt pathway in GCS self-renewal and tumorigenicity, and might represent the starting point for the development of more potent and focused multi-target therapies for GBM.
AB - Aggressive behavior and diffuse infiltrative growth are the main features of Glioblastoma multiforme (GBM), together with the high degree of resistance and recurrence. Evidence indicate that GBM-derived stem cells (GSCs), endowed with unlimited proliferative potential, play a critical role in tumor development and maintenance. Among the many signaling pathways involved in maintaining GSC stemness, tumorigenic potential, and anti-apoptotic properties, the PDK1/Akt pathway is a challenging target to develop new potential agents able to affect GBM resistance to chemotherapy. In an effort to find new PDK1/Akt inhibitors, we rationally designed and synthesized a small family of 2-oxindole derivatives. Among them, compound 3 inhibited PDK1 kinase and downstream effectors such as CHK1, GS3Kα and GS3Kβ, which contribute to GCS survival. Compound 3 appeared to be a good tool for studying the role of the PDK1/Akt pathway in GCS self-renewal and tumorigenicity, and might represent the starting point for the development of more potent and focused multi-target therapies for GBM.
KW - GBM stem cells
KW - Glioblastoma
KW - Kinase inhibitors
KW - Multi-target therapy
KW - Oxindole derivatives
KW - PDK1 inhibitors
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U2 - 10.1016/j.ejmech.2015.10.020
DO - 10.1016/j.ejmech.2015.10.020
M3 - Article
C2 - 26498573
AN - SCOPUS:84944897843
VL - 105
SP - 274
EP - 288
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -