Organic Synthesis to help treat Lung Cancer

Background - Why is this important?

Cancer refers to a wide group of diseases caused by cells that divide uncontrollably. It has been estimated that lung cancer kills more people than any other form of cancer. An estimated 1.61 million people across the world were diagnosed with lung cancer in 2008, accounting for 13% of the total cancer cases.1 New medicines are desperately needed. Fortunately this is one of the most active areas of research for drug discovery.

Whilst we still have some way to go to achieve a tablet to cure the disease there was a breakthrough in 2011. Anaplastic lymphoma kinase (ALK) is an enzyme, a protein that acts as a chemical messenger with a fundamental role in many cellular processes. ALK activity is tightly controlled in normal cells. However, scientists knew that a small sub group of patients with lung cancer had a genetic abnormality that increased the activity of this enzyme. This implicated ALK in the development and progression of lung cancer. Blocking ALK activity with crizotinib can stop cells growing, this triggered a race to discover the first selective ALK inhibitor drug.

What did the organic chemists do?

Modern chemistry research plays a crucial role in improving both diagnosis and treatment. Given the aim of discovering a selective ALK inhibitor, research scientists began by designing and making just a few milligrams of several thousand new compounds before they found the magic bullet suitable for testing in patients. As soon as this milestone was reached organic chemists needed to devise a new method to rapidly make much larger quantities (kg) which would be needed for clinical trials. This raised new challenges, safety, environmental impact and speed. Skilled organic chemists working in the UK used the latest developments in synthetic organic chemistry to devise a new method involving just three chemical reactions to make the key building block for crizotinib, the piperidine shown below. The new drug was tested successfully in lung cancer patients in clinical trials.

Picture: Crozitinib (Xalkori TM) - a treatment for certain late-stage lung cancer

What was the impact?

“I felt like I had won the lottery when I found I had this gene”

Diane Butelli, Lung cancer patient

Following FDA approval in 2011, crizotinib (Xalkori^TM) was launched in the USA to treat certain late-stage lung cancers. Crizotinib is only given to the ~5% of patients who have this abnormal ALK genetic diagnosis. Drugs of this type are referred to as ‘personalised medicines’ because they are targeted to just the sub-group of patients who will benefit from taking the medicine.

This success demonstrates how the study of DNA-associated abnormalities allows drugs to become more specialised to genetic subgroups, as a result treatment can be targeted to patients that will receive the most benefit. Further clinical trials are underway to explore additional uses of crizotinib and to make it available for patients in other countries.