1:36 PM
Apr 13, 2017
 |  BC Innovations  |  Targets & Mechanisms

Allosteric en-ABL-ement

Why Novartis is combining allosteric and catalytic site ABL inhibitors in CML

Novartis AG has developed a new strategy to prevent leukemias from becoming resistant to its CML drugs against BCR-ABL. Rather than combining the inhibitors with other classes of cancer therapies, the company is doubling its attack on the target with compounds that hit the allosteric and catalytic sites.

Novartis markets Gleevec imatinib and Tasigna nilotinib to treat chronic myelogenous leukemia (CML) and other hematologic malignancies. Although the drugs revolutionized treatment of the disease, they both target the catalytic site of BCR-ABL, and are vulnerable to resistance mutations that can arise in the site, causing patients to relapse.

One way to tackle the problem is to follow the first drug with a second that acts via a different mechanism. While that can buy patients time, cancer cells often end up developing resistance to the second drug as well.

A second strategy is to combine a BCR-ABL inhibitor with another drug from the outset, reducing the odds the cancer has time to develop mutations to both molecules before it is eradicated. However, in cancers driven by BCR-ABL, not many other targets have been as well-validated.

Last month in Nature, Novartis described an approach that involves attacking only BCR-ABL, but with both an allosteric and catalytic site inhibitor.

Andrew Wylie, a senior investigator at Novartis and author on the study, told BioCentury the idea is to "increase coverage" of the target so that any single mutation would be very unlikely to yield resistance to...

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