Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme.
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.
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
Simona
S
Sestito
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
Giulia
G
Nesi
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
Simona
S
Daniele
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
Alma
A
Martelli
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
Maria
M
Digiacomo
Alidans S.r.l., Via Vecchializia, 48, 56017 San Giuliano Terme, PI, Italy.
Alice
A
Borghini
Alidans S.r.l., Via Vecchializia, 48, 56017 San Giuliano Terme, PI, Italy.
Daniele
D
Pietra
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
Vincenzo
V
Calderone
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
Annalina
A
Lapucci
Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute Biosciences, Curtin University, Perth, Western Australia 6102, Australia.
Marco
M
Falasca
Laboratory of Oncology, Hospital "Casa Sollievo Della Sofferenza", Viale Cappuccini, 1, 71013 San Giovanni Rotondo, FG, Italy.
Paola
P
Parrella
Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, I-71013 San Giovanni Rotondo, FG, Italy.
Angelantonio
A
Notarangelo
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
Maria C
MC
Breschi
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
Marco
M
Macchia
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
Claudia
C
Martini
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy. Electronic address: simona.rapposelli@farm.unipi.it.
Simona
S
Rapposelli
D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
D007211:Indoles; D000078183:Oxindoles; C000631429:PDK1 protein, human; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C022960:2-oxindole; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt
GBM stem cells; Glioblastoma; Kinase inhibitors; Multi-target therapy; Oxindole derivatives; PDK1 inhibitors