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Pfizer Goes The Kinase Route In Lung Cancer

The American Society of Clinical Oncology (ASCO) meeting in Chicago has been dominating pharma news for the past few days. And while much of the cancer-drug-related news coming out of the meeting is about biologics, the small molecule crizotinib is in the spotlight, too. Crizotinib is an experimental drug that Pfizer is developing for the treatment of lung cancer in a very specific set of patients.

Much of the crizotinib coverage focuses on its targeting of anaplastic lymphoma kinase. While many “targeted” drugs have reached the market in recent years, very few types of cancer are driven by a single genetic mutation, so the drugs’ effect has therefore been limited. One of the rare exceptions is Novartis’ drug Gleevec, which targets a protein kinase called BCR-ABL. Gleevec has been called a miracle drug for its ability to halt a rare type of leukemia; some scientists now think crizotinib could be another of those rare exceptions. Robert Langreth at Forbes quotes Mark Kris, a scientist at Memorial Sloan-Kettering Cancer Center, who likens crizotinib to Gleevec.

While it’s too early to compare an experimental therapy like crizotinib to Gleevec, a successful marketed drug that has had a major impact on cancer research, at a molecular level, Kris is right, since both drugs do go after kinases.

Crizotinib is designed to work on the ~3-5% of lung cancer patients with an alteration in the ALK gene- that’s roughly 10,000 people in the USA, according to the Wall Street Journal. WSJ has articles on crizotinib here and here.

Now, when I see the word kinase, the first place I hunt for information are the archives of KinasePro. That didn’t disappoint- and revealed some more details of the drug’s story.

According to a discussion on KinasePro, the patent literature reveals that the series of compounds that included the future crizotinib was discovered by scientists at Sugen, a company which Pfizer acquired. We alluded to the fact that Pfizer inherited many such molecules in our coverage of drugs targeting Met, a tyrosine-kinase receptor implicated in many cancers. As the WSJ noted, crizotinib’s activity against Met, which was the reason Pfizer acquired it in the first place, has so far turned out to be less important than its effects on ALK. It’s worth noting that Gleevec targets other kinases as well- it’s not perfectly selective for BCR-ABL.

Is there a lesson for cancer research in here? Is high selectivity for one molecular target necessarily a good thing in drug development?

Bonus: If you want to get a real feel for the ‘needle in the haystack’ exercise that pharma is, try downloading the 2004 patent that KinasePro cites as the earliest mention of the series. It’s 300 pages long and packed with compounds, most of which will never get anywhere near a person, let alone a pharmacy shelf.

Structure credit:Biochemistry

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