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.