The effect of PLC-γ2 inhibitors on the growth of human tumour cells.
The phosphoinositide specific-phospholipase C-γ (PLC-γ1 and 2) enzymes are plausible anticancer targets implicated in cell motility important to invasion and dissemination of tumour cells. A host of known PLC-γ2 inhibitors were tested against the NCI60 panel of human tumour cell lines as well as their commercially available structural derivatives. A class of thieno[2,3-b]pyridines showed excellent growth arrest with derivative 3 giving GI(50) = 58 nM for the melanoma MDA-MB-435 cell line. The PLC-γ2 is uniquely expressed in haematopoietic cells and the leukaemia tumour cell lines were growth restricted on average GI(50) = 275 nM by derivative 3 indicating a specific interaction with this isoform. Furthermore, a moderate growth inhibition was found for compound classes of indoles and 1H-pyrazoles. It is likely that the active compounds do not only inhibit the PLC-γ2 isoform but other PLCs as well due to their conserved binding site. The compounds tested were identified by applying the tools of chemoinformatics, which supports the use of in silico methods in drug design.
School of Chemical Sciences, The University of Auckland, Auckland, New Zealand.
Linda
L
Feng
Inga
I
Reynisdóttir
Jóhannes
J
Reynisson
D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000473:pathology*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058924:Thienopyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007211:Indoles; D010069:Oxadiazoles; D011720:Pyrazoles; D058924:Thienopyridines; D051966:Phospholipase C gamma