Novel pocket spotted

Researchers have identified a new class of chemicals that bind to a previously unknown allosteric pocket-a pocket outside the enzyme active site-and inhibit the enzyme FPPS. The work could have implications for new treatments of bone diseases, Paget's disease and tumour-induced bone degradation.

Approved nitrogen-containing bisphosphonates are potent inhibitors of the enzyme farnesyl pyrophosphate synthase (FPPS) and are highly effective in treating bone diseases such as osteoporosis, and bone degradation caused by cancer. However, the identification of a new class of chemicals that bind to and inhibit a previously unknown allosteric pocket of this enzyme, a pocket that lies outside the enzyme active site, could represent useful leads that might change the efficacy and side-effects profiles of drugs that target FPPS. FPPS is an enzyme involved in lipid formation and is a potential target for a wide range of diseases.

Bisphosphonates - a class of FDA-approved drugs that are effective in the treatment of bone diseases such as osteoporosis-are potent inhibitors of FPPS. It has been thought that bisphosphonates could be used as antitumor agents, but the high attraction of this class of chemicals to bone mineral makes them unsuitable for targeting most tumours. Using a combination of NMR spectroscopy and X-ray crystallography, Wolfgang Jahnke and colleagues identify a novel allosteric binding pocket that permits the inhibition of FPPS by new non-bisphosphonate types of chemicals. This finding opens up opportunities for further validation of FPPS as an anti-cancer target.

Wolfgang Jahnke, Jean-Michel Rondeau, Simona Cotesta, Andreas Marzinzik, Xavier Pellé, Martin Geiser, André Strauss, Marjo Götte, Francis Bitsch, René Hemmig, Chrystèle Henry, Sylvie Lehmann, Fraser Glickman, Tthomas Roddy, Steven Stout, and Jonathan Green of the Center For Proteomic Chemistry And Global Discovery Chemistry, at Novartis Institutes For Biomedical Research, in Basel, Switzerland, describe details in the journal Nature Chemical Biology. They explain that in contrast to other lipophilic drugs, bisphosphonates have a high degree of charge and so are water-soluble molecules. As such, they can only enter cells such as osteoclasts and macrophages. But, their high affinity for bone mineral means they rapidly accumulate at sites of active bone turnover, which is what their developers desired in terms of drugs for bone disease.

The researchers explain that the potential for these same compounds as antitumour agents hinges on several pre-clinical studies. Indeed, disease progression in premenopausal breast cancer patients has been seen to respond to endocrine therapy and zoledronic acid, which has also stimulated interest in these compounds. Moreover, data suggesting that the cholesterol-controlling statins, which also inhibit the mevalonate pathway by enzyme inhibition upstream of FPPS, may have antitumour properties. That work corroborates the importance of the mevalonate pathway as a clinically relevant antitumour target, the team says, pointing out that bisphosphonates by inhibiting FPPS in osteoclasts, also inhibit the mevalonate pathway.

Although FPPS represents a useful anticancer target, the fact that nitrogen-containing bisphosphonates have high bone affinity had, until now precluded their development for cancer therapy. The Swiss team's work using fragment-based drug screening, shows that there are non-bisphosphonate inhibitors that bind in a previously undescribed allosteric pocket and so avoid this problem. The natural function of this allosteric pocket remains an unknown for the time being.

"The discovery of non-bisphosphonate FPPS inhibitors is an example of the successes and surprises encountered when applying modern drug discovery technologies to well-known targets," the team says. "After decades of futile attempts to modify the bisphosphonate moiety in order to identify new classes of FPPS inhibitors with different pharmacokinetic properties, the discovery of the allosteric pocket and potent non-bisphosphonate inhibitors is a breakthrough in the ongoing search for new antitumour drugs based on FPPS inhibition."

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