A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D.
The PPM1D gene is aberrantly amplified in a range of common cancers and encodes a protein phosphatase that is a potential therapeutic target. However, the issue of whether inhibition of PPM1D in human tumour cells that overexpress this protein compromises their viability has not yet been fully addressed. We show here, using an RNA interference (RNAi) approach, that inhibition of PPM1D can indeed reduce the viability of human tumour cells and that this effect is selective; tumour cell lines that overexpress PPM1D are sensitive to PPM1D inhibition whereas cell lines with normal levels are not. Loss of viability associated with PPM1D RNAi in human tumour cells occurs via the activation of the kinase P38. To identify chemical inhibitors of PPM1D, a high-throughput screening of a library of small molecules was performed. This strategy successfully identified a compound that selectively reduces viability of human tumour cell lines that overexpress PPM1D. As expected of a specific inhibitor, the toxicity to PPM1D overexpressing cell lines after inhibitor treatment is P38 dependent. These results further validate PPM1D as a therapeutic target and identify a proof-of-principle small molecule inhibitor.
Rayter
S
S
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
Elliott
R
R
Travers
J
J
Rowlands
M G
MG
Richardson
T B
TB
Boxall
K
K
Jones
K
K
Linardopoulos
S
S
Workman
P
P
Aherne
W
W
Lord
C J
CJ
Ashworth
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000071636:Protein Phosphatase 2C
D000970:Antineoplastic Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; C007201:cyclopentanone; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C