Antibiotic Targets "Undruggable” Cancer Proteins

A team of molecular biologists has found that an immunosuppressive antibiotic blocks the activity of an enzyme that is highly expressed in several types of cancer and may have potential as an anticancer therapeutic agent.

The drug, tautomycetin (TTN), is closely related to tautomycin a drug produced by Streptomyces that is a very potent inhibitor of the protein phosphatases PP1 and PP2A. In addition to its antibiotic properties, TTN is highly immunosuppressive and is used in organ transplantation.

Investigators at the Indiana University School of Medicine (Indianapolis, USA) reported in the January 28, 2011, issue of the journal Chemistry and Biology that the cellular target of TTN was the enzyme SHP2 (also known as protein tyrosine phosphatase, nonreceptor type 11 or PTP). SHP2 phosphatase is a positive transducer of growth factor and cytokine signaling as well as being a bona fide oncogene. Gain-of-function SHP2 mutations leading to increased phosphatase activity cause Noonan syndrome, as well as multiple forms of leukemia and solid tumors.

In the current study, the investigators showed that tautomycetin and its genetically engineered analog TTN D-1 were potent SHP2 inhibitors. X-ray crystallography studies revealed that TTN D-1 occupied the SHP2 active site in a manner similar to that of a peptide substrate.

"Dysregulation of PTP activity has been linked to several human diseases, including cancer, diabetes, and immune dysfunctions. But their makeup has made it difficult to find potential drugs to act on them, characteristics that have labeled the PTPs as ‘undruggable',” said senior author Dr. Zhong-Yin Zhang professor of biochemistry and molecular biology at the Indiana University School of Medicine. "So we have identified a lead – a natural product produced by the bacteria Streptomyces – that should serve as a foundation for the development of therapeutic agents for a large family of protein tyrosine phosphotase targets. Until now these targets, including SHP2 for leukemia and other cancers, have been deemed undruggable.”

Related Links:
Indiana University School of Medicine