November 2009

Cecil Pickett: Advancing Drug Metabolism and Discovery

pickett
Cecil Pickett gives a lecture during university week.

“During my studies of the association between mitochondria and endoplasmic reticulum, I had become interested in cytochrome P-450, as its biosynthesis was connected with the formation of endoplasmic reticulum-mitochondria complexes,” Pickett says. “And Lu was a noted expert in P-450 biochemistry.” Together, they formed a collaboration to try to quantify the activity of specific cytochrome P-450 enzymes after exposure to xenobiotics. This was a vital enterprise, as P-450 enzymes are the major elements involved in drug metabolism, and understanding P-450 interactions is critical in determining proper drug dosage and identifying any risks of multidrug regimens.

“This has been one area that often gets overlooked in discussing the advances made by the pharmaceutical industry,” Pickett says. “When I first started in industry, the role of cytochrome P-450 enzymes was largely unknown. Today, however, for every drug we develop, we know exactly which P-450 enzyme metabolizes it.”

Climbing the Ladder 

Over the next three decades, Pickett remained embedded in industry, although the names and places changed as he progressed upward. After his initial assignment serving with Alberts on the development team working on the first generation HMG-CoA reductase inhibitors (statins), Pickett soon rose to the position of director of the department of molecular pharmacology and biochemistry. In 1988, he moved to Montreal to become the head of research at the Merck Frosst Centre for Therapeutic Research, where, among other duties, he recruited bright scientific minds — looking for the next Cecil Pickett, as it were. It was during his tenure that Merck Frosst researchers discovered the asthma drug Singulair. (Homage to the site of discovery can be found in the drug’s scientific name, Montelukast).

“It was becoming obvious to Merck that Cecil could lead any drug research group,” says Vagelos about his longtime colleague, “and unfortunately for Merck this was becoming apparent to others as well.”

In 1993, Pickett left Merck to become executive vice president of discovery research at the Schering-Plough Research Institute in Kenilworth, N.J., where he oversaw the planning for the company’s drug-discovery program. “After 15 years at Merck, during which time I had seen Vagelos really transform the company, I thought it would be a great challenge to help build up another organization.”

Pickett experienced great success over the next several years, which saw the development of drugs like the cholesterol absorption inhibitor Zetia and the antifungal Noxafil, and he also expanded the breadth of the drug-discovery program to include targeting central nervous system disorders. Such contributions would earn him another promotion in 2002, this time to president of the Schering-Plough Research Institute, putting him in charge of all aspects of research and development.

Despite ever-increasing administrative duties with each passing promotion, Pickett continued to oversee his own laboratory and independent research into drug metabolism. After completing his work with cytochrome P-450, he began studying glutathione-S-transferases (GSTs), another important family of enzymes involved in drug modification and metabolism. Pickett’s lab was one of the first to clone the cDNA for GST proteins, characterize their genes and examine the regulation of their expression in response to xenobiotics and oxidative stress. More recently, he also has taken a closer look at Nrf2, a transcription factor that has emerged as the master regulator of the antioxidant response.

“His dedication to research was one of the things I most admire about Cecil,” says colleague Fred Guengerich of Vanderbilt School of Medicine, “especially since it carried into other areas. When it came time to make a difficult decision regarding advancing a drug, he always held true to the science.”

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