Discovery of indoline-based, natural-product-like compounds as probes of focal adhesion kinase signaling pathways.
With the goal of identifying small molecule modulators of protein-protein interactions, we developed a solid-phase synthesis method, which was then successfully utilized in a library generation of 164 aminoindoline-derived, natural-product-like compounds. This library and several other related intermediates synthesized during this project were then subjected to different biological assays in search of small molecule modulators of focal adhesion kinase (FAK)-mediated signaling pathways. This study included (i) an in vitro, full length FAK inhibition assay, (ii) a cell proliferation assay, and (iii) a wound healing assay. In FAK inhibition assay, eight library members (5-12) and three aminoindoline derivatives (13, 14, and 2) were identified as promising candidates. Compounds 13 and 2 inhibited the FAK activity by 25-45% at 10 microM. These two lead compounds also showed activity in a wound healing assay. To our knowledge, these aminoindoline-derived small molecules belong to a new family of FAK inhibitors.
Poondra
Rajamohan R
RR
Steacie Institute for Molecular Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, Ontario, Canada.
Kumar
N Niranjan
NN
Bijian
Krikor
K
Prakesch
Michael
M
Campagna-Slater
Valérie
V
Reayi
Ayub
A
Reddy
P Thirupathi
PT
Choudhry
Asna
A
Barnes
Michael L
ML
Leek
Donald M
DM
Daroszewska
Malgosia
M
Lougheed
Caroline
C
Xu
Bin
B
Schapira
Matthieu
M
Alaoui-Jamali
Moulay A
MA
Arya
Prabhat
P
D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects
D007211:Indoles; D054852:Small Molecule Libraries; C057812:indoline; D051416:Focal Adhesion Protein-Tyrosine Kinases