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

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.