NEWS OF THE WEEK NH2
H2N
AGENTS LAND ON RAS RUNWAY DRUG DISCOVERY: Cyclic peptides stymie cancer-associated Ras proteins
M
UTATED RAS signaling proteins, frequently
found in human cancer cells, are like airports with hard-to-find runways. They lack prominent binding sites for small molecules, so prospective anticancer drugs don’t land there very often. None has ever been approved commercially, despite decades of effort. Dehua Pei, Roger Briesewitz, and coworkers at Ohio State University have now identified a group of cyclic peptides that inhibit several forms of human Ras (Angew. Chem. Int. Ed. 2015, DOI: 10.1002/anie.201502763). The peptides permeate cancer cells readily and inhibit Ras signaling inside the cells with moderate potency. Then they cause cell death. At least 52 mutated, overactive forms of Ras are associated with about 30% of human cancers. Scientists have already identified small druglike molecules that bind Ras mutants weakly. They’ve also singled out some compounds that inhibit Ras mutants indirectly, such as by blocking the mutants from cell membranes, where signaling occurs, or by obstructing signaling partners. But none has survived clinical trials. Only a few potent and direct Ras inhibitors have been found. Among the best are agents that bond covalently to K-Ras(G12C), a mutated human Ras protein associated with lung cancer. Two teams—one led by Kevan M. Shokat of the University of California, San Francisco, and the other by Nathanael S. Gray of Harvard Medical School—independently discovered
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O covalent inhibitors of O O K-Ras(G12C) in 2013 H NH2 N NH (Nature, DOI: 10.1038/ O N nature12796; Angew. H NH O O Chem. Int. Ed., DOI: 10.1002/ anie.201307387). Drug candiNH NH O O dates based on the inhibitors O H could move into clinical trials O N N O but are likely to inhibit only NH H H N that single Ras mutant. N N H By screening a O OH H N H2N N large collection of NH2 N cyclic peptides, Pei, NH2 H N NH 2 2 Briesewitz, and coworkNH2 ers have now found direct inhibitors for multiple Ras mutants: Some of the This is the best prospect so far peptides kill lung cancer cells with either of two differamong the newly ent Ras mutations, some kill pancreatic cancer cells identified cancerwith a third Ras mutation, and others bind to two classes fighting cyclic of wild-type (nonmutated) Ras. Ohio State’s Drug peptide mutantDevelopment Institute is collaborating with Evotec, in Ras inhibitors. Hamburg, Germany, to develop the inhibitors. “We don’t know if inhibition of wild-type Ras in normal cells will be tolerated” in the body, Briesewitz says. “But our compounds are a good start, and we may be able to make them mutation-specific,” thus sparing wild-type Ras protein, which plays an essential role in normal cell signaling processes. “There may also be ways to deliver our Ras inhibitors selectively to cancer cells.” “The results are promising,” comments Ras specialist Herbert Waldmann of the Max Planck Institute of Molecular Physiology, in Dortmund, Germany. But he notes that what the Ohio State group hasn’t yet addressed and “what will be absolutely required” moving forward is to evaluate the cyclic peptides inside living organisms. Shokat adds that the lack of in vivo data doesn’t concern him yet because “the cellular data are quite impressive.”—STU BORMAN
FINE CHEMICALS BASF to sell custom synthesis and API businesses to Siegfried BASF says it plans to sell its custom synthesis business and part of its active pharmaceutical ingredients (API) business to Siegfried Holding, the Swiss parent company of the drug chemical producer Siegfried. The deal, involving manufacturing sites in Germany, Switzerland, and France, will affect about 850 employees. Siegfried will pay BASF $306 million. The acquisition will increase Siegfried’s sales by roughly 50% to $955 million. BASF, the world’s largest chemical company, says it wants to focus its API and services operations within its nutrition and health division, and will retain generic API businesses only where it holds
a leading market position. These include ibuprofen, omega-3 fatty acids, and polyethylene glycol. APIs that will go to Siegfried include ephedrine, pseudoephedrine, and caffeine. The divestiture will follow BASF’s sale of its Knoll Pharmaceuticals business to Abbott Laboratories, now Abbott, for $6.9 billion, in 2000, and its acquisition of Swiss pharmaceutical contract manufacturer Orgamol in 2005. BASF will join Dow Chemical, Eastman Chemical, Rhodia, and most recently DSM among the major diversified chemical companies to exit custom synthesis. “This step is in line with BASF’s strategy
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of actively managing its portfolio,” says Michael Heinz, a member of the board of executive directors at BASF. He adds that it will focus the company’s performance chemicals unit on “high-margin core businesses.” Fine chemicals market analyst Jan Ramakers says he was “a bit surprised” by the news, especially given the acquisition of Orgamol. Selling off Knoll, a finished drug product business, made sense, he says. But custom synthesis and generic APIs seem to fit the company’s integrated business model. BASF and Siegfried say they plan to transfer employees affected by the deal to Siegfried.—RICK MULLIN
