Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 274-288 |
| Number of pages | 15 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 105 |
| DOIs | |
| Publication status | Published - Nov 13 2015 |
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Keywords
- GBM stem cells
- Glioblastoma
- Kinase inhibitors
- Multi-target therapy
- Oxindole derivatives
- PDK1 inhibitors
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry
- Pharmacology
Cite this
Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme. / Sestito, Simona; Nesi, Giulia; Daniele, Simona; Martelli, Alma; Digiacomo, Maria; Borghini, Alice; Pietra, Daniele; Calderone, Vincenzo; Lapucci, Annalina; Falasca, Marco; Parrella, Paola; Notarangelo, Angelantonio; Breschi, Maria C.; Macchia, Marco; Martini, Claudia; Rapposelli, Simona.
In: European Journal of Medicinal Chemistry, Vol. 105, 13.11.2015, p. 274-288.Research output: Contribution to journal › Article
}
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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UR - http://www.scopus.com/inward/citedby.url?scp=84944897843&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2015.10.020
DO - 10.1016/j.ejmech.2015.10.020
M3 - Article
VL - 105
SP - 274
EP - 288
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -