Building skeletally diverse architectures on the Indoline Scaffold: the discovery of a chemical probe of focal adhesion kinase signaling networks.
Inspired by bioactive indoline alkaloid natural products, here, we report a divergent synthesis approach that led to skeletally diverse indoline alkaloid-inspired compounds. The natural product-inspired compounds obtained were then subjected to a series of in vitro and cellular assays to examine their properties as modulators of focal adhesion kinase (FAK) activity. This study resulted in the identification of a promising lead inhibitor of FAK (42), which also showed activity in a wound healing and cell invasion assay. The in silico study of the lead compound (42) was also undertaken.
Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Toronto, Ont., Canada M5G0A3.
Michael
M
Prakesch
Krikor
K
Bijian
Valérie
V
Campagna-Slater
Sophie
S
Quevillon
Reni
R
Joseph
Chang-Qing
CQ
Wei
Esther
E
Sesmilo
Ayub
A
Reayi
Rajamohan R
RR
Poondra
Michael L
ML
Barnes
Donald M
DM
Leek
Bin
B
Xu
Caroline
C
Lougheed
Matthieu
M
Schapira
Moulay
M
Alaoui-Jamali
Prabhat
P
Arya
D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000187:drug effects
D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D007211:Indoles; C057812:indoline; D051416:Focal Adhesion Protein-Tyrosine Kinases