A small molecule inhibitor of p53-inducible protein phosphatase PPM1D

Hiroaki Yagi; Yoshiro Chuman; Yuuki Kozakai; Toshiaki Imagawa; Yu Takahashi; Fumihiko Yoshimura; Keiji Tanino; Kazuyasu Sakaguchi

doi:10.1016/j.bmcl.2011.10.084

A small molecule inhibitor of p53-inducible protein phosphatase PPM1D

Bioorg Med Chem Lett. 2012 Jan 1;22(1):729-32. doi: 10.1016/j.bmcl.2011.10.084. Epub 2011 Oct 31.

Authors

Hiroaki Yagi¹, Yoshiro Chuman, Yuuki Kozakai, Toshiaki Imagawa, Yu Takahashi, Fumihiko Yoshimura, Keiji Tanino, Kazuyasu Sakaguchi

Affiliation

¹ Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, North 10, West 8, Kita-ku, Hokkaido University, Sapporo 060-0810, Japan.

PMID: 22115592
DOI: 10.1016/j.bmcl.2011.10.084

Abstract

PPM1D is a p53-inducible Ser/Thr protein phosphatase. PPM1D gene amplification and overexpression have been reported in a variety of human tumors, including breast cancer and neuroblastoma. Because the phosphatase activity of PPM1D is essential for its oncogenic role, PPM1D inhibitors should be viable anti-cancer agents. In our current study, we showed that SPI-001 was a potent and specific PPM1D inhibitor. SPI-001 inhibited PPM1D phosphatase activity in PPM1D-overexpressing human breast cancer cells and increased phosphorylation of p53. Furthermore, SPI-001 suppressed cell proliferation by inducing apoptosis. Our present study suggested that SPI-001 was a potential lead compound in developing anti-cancer drugs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Apoptosis
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation
DNA-Binding Proteins / metabolism
Dose-Response Relationship, Drug
Humans
Indoles / pharmacology
Inhibitory Concentration 50
Models, Chemical
Neoplasms / drug therapy*
Phenanthrenes / pharmacology*
Phosphoprotein Phosphatases / antagonists & inhibitors*
Phosphoric Monoester Hydrolases / chemistry
Phosphorylation
Protein Phosphatase 2C
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins pp60(c-src) / metabolism
Time Factors
Tumor Suppressor Protein p53 / metabolism*
Tumor Suppressor Proteins / metabolism

Substances

Antineoplastic Agents
Cell Cycle Proteins
DNA-Binding Proteins
Indoles
Phenanthrenes
SPI-001
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
DAPI
MATK protein, human
Proto-Oncogene Proteins pp60(c-src)
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
Protein Serine-Threonine Kinases
PPM1D protein, human
Phosphoprotein Phosphatases
Protein Phosphatase 2C
Phosphoric Monoester Hydrolases