Novartis First-Generation Lung Cancer Drug Tweaked To Reduce Potential Side Effects | Chemical & Engineering News
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Web Date: June 20, 2013

Novartis First-Generation Lung Cancer Drug Tweaked To Reduce Potential Side Effects

Medicinal Chemistry: Redesigned enzyme inhibitor designated as breakthrough therapy by FDA
Department: Science & Technology | Collection: Life Sciences
News Channels: Biological SCENE, Organic SCENE
Keywords: cancer drug, ALK inhibitor, Novartis, TAE684, LDK378, non-small-cell lung cancer
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IMPROVING A DRUG
Novartis’ first-generation inhibitor of the enzyme anaplastic lymphoma kinase (TAE684, left) formed potentially harmful protein adducts in the body. To reduce side effects, chemists moved the position of a troublesome nitrogen to make the current version of the drug (LDK378, right).
Credit: J. Med. Chem.
Structures of anaplastic lymphoma kinase inhibitors
 
IMPROVING A DRUG
Novartis’ first-generation inhibitor of the enzyme anaplastic lymphoma kinase (TAE684, left) formed potentially harmful protein adducts in the body. To reduce side effects, chemists moved the position of a troublesome nitrogen to make the current version of the drug (LDK378, right).
Credit: J. Med. Chem.

Certain lung cancer tumors express an enzyme called anaplastic lymphoma kinase (ALK), which is critical to the cancer’s survival and spread. As a result, ALK is a popular drug target. Now researchers describe how they redesigned an ALK inhibitor to avoid toxicity issues and produce a promising drug (J. Med. Chem. 2013, DOI: 10.1021/jm400402q). The new inhibitor, currently in clinical trials to treat non-small-cell lung cancer, is on fast-track review with the Food and Drug Administration.

In 2007, researchers at the Genomics Institute of the Novartis Research Foundation reported a potent ALK inhibitor (Proc. Nat. Acad. Sci. 2007, DOI: 10.1073/pnas.0609412103) that had “a serious liability,” says Pierre-Yves Michellys, director of medicinal chemistry at GNF. In the body, the compound’s electron-rich aniline group tends to change into a highly reactive quinone that can bind to nontarget proteins. Michellys and his colleagues determined that the key to this reactivity lies with a nitrogen atom connected to the aniline ring.

So they designed a set of variations on the compound with the nitrogen in a different position. These new drug contenders lacked the tendency to react with proteins. One variation, LDK378, turned out to be extremely selective for ALK. In rats injected with ALK-positive cancers, the compound significantly shrunk or even totally eliminated tumors.

The FDA recently designated LDK378 as a breakthrough therapy based on encouraging results from early clinical trials in patients with ALK-positive, non-small-cell lung cancer.

 
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Comments
nancy (October 24, 2013 1:45 AM)
is there any possible to cure lung cancer[stage 4]

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