Novel inhibitors targeting PPM1D phosphatase potently suppress cancer cell proliferation.

Abstract

Protein phosphatase magnesium-dependent 1δ (PPM1D, Wip1) is a p53 inducible serine/threonine phosphatase. PPM1D is a promising target protein in cancer therapy since overexpression, missense mutations, truncating mutations, and gene amplification of PPM1D are reported in many tumors, including breast cancer and neuroblastoma. Herein, we report that a specific inhibitor, SL-176 that can be readily synthesized in 10 steps, significantly inhibits proliferation of a breast cancer cell line overexpressing PPM1D and induces G2/M arrest and apoptosis. SL-176 decreases PPM1D enzyme activity potently and specifically in vitro. These results demonstrate that SL-176 could be a useful lead compound in the development of effective anti-cancer agents.

• Authors: Sari Ogasawara, Yuhei Kiyota, Yoshiro Chuman, Ayano Kowata, Fumihiko Yoshimura, Keiji Tanino, Rui Kamada, Kazuyasu Sakaguchi
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 19 Pg. 6246-9 (Oct 01 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 26358280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Tumor Suppressor Protein p53
• PPM1D protein, human
• Phosphoprotein Phosphatases
• Protein Phosphatase 2C

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme Inhibitors (chemistry, pharmacology)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• M Phase Cell Cycle Checkpoints (drug effects)
• Phosphoprotein Phosphatases (antagonists & inhibitors, metabolism)
• Protein Phosphatase 2C
• Tumor Suppressor Protein p53 (metabolism)