New designs on imatinib

COURTESY OF ELSEVIER

The paper:

The finding:

Imatinib (Gleevec) stunned the world with its high cure rate for chronic myeloid leukemia through the inhibition of tyrosine kinase Bcr-Abl. But, BCR-ABL mutations are a common cause of relapse during therapy. Working from imatinib's structure, researchers affiliated with Harvard University and Novartis developed AMN107, which is roughly 20 times as potent as imatinib and active against most imatinib-resistant Bcr-Abl mutations.

The follow-up:

AMN107, now known as nilotinib (Tasigna), has completed Phase II clinical trials and is awaiting FDA and EU review as a new drug for chronic myeloid leukemia.

The verdict:

Brian Druker at Oregon Health & Science University in Portland says their use of imatinib's crystal structure in the design process was both interesting and trendsetting. "It announced that structure-based drug design had arrived," he says.

The work ahead:

One of the most prevalent and highly imatinib-resistant mutations, T315I, remains impervious to nilotinib, as well as another compound designed to overcome imatinib resistance, dasatinib. "Drug companies are now lining up to overcome this one particular mutant," says Ellen Weisberg at Dana Farber Cancer Institute, Boston.