William Baker discovered his passion for chemistry the first time he saw the crystals of a drug molecule through the microscope. He was drawn to the artistic side of making molecules – the designs, colors, and shapes– and excited by the idea of creating completely novel 3-D structures. “It is like mini-architecture,” he says.
So, it isn’t surprising that in 1993, when he and colleague Ken Stover, Ph.D. first saw the structure of CGI 17341, an lead antitubercular compound from Ciba Giegy, Baker saw something that no one else had imagined, a new chemical series. While Stover mulled the molecule’s biology and bacterial target, Baker was fascinated by its 3-D structure and chemistry. Their different approaches resulted in the exciting discovery of the promising new antitubercular compound, PA-824.
“That marriage of thinking differently really is what created 824,” says Baker, now vice president of research for Corus Pharma in Seattle and a pro-bono consultant for PA-824 with the TB Alliance.
Now about to enter the clinical phase, PA-824’s potential as a TB drug has been well documented in in vitro and in vivo tests. Baker is quite enthusiastic about PA-824’s ability to kill tuberculosis in its dormant state, a problem that has vexed scientists for decades. Dormant TB has few ongoing biological processes and cells do not actively replicate, according to Baker. Consequently, there are fewer targets for drugs to hit. PA-824 succeeds because it has a unique mechanism of action that is very effective against the bacterium at the dormant stage.
“This is the first new drug that can kill both replicating and dormant phase TB,” he says. “And now, it’s about to be tested in humans. It’s gone down a long road from our work in the early 1990s.”
In 2000, after Chiron Corporation acquired PA-824, they licensed the development of the compound to the Global Alliance for TB Drug Development. The TB Alliance has moved PA-824 rapidly through the development process and it is expected to enter Phase I clinical trials in the summer of 2005.
“Clearly the TB Alliance’s goal was to develop PA-824 for registration,” says Baker, who received his doctorate in organic chemistry from the University of Illinois Champaign. “Without the involvement of the Alliance, I am certain that this promising antitubercular drug would have languished in pharmaceutical limbo, never to see the light of day again. We can now imagine its use for solving one of the world’s most pressing global health issues.”
When Baker was asked to become a consultant for the PA-824 program last year, he leapt at the opportunity to get involved again in a project that had been very important to him.
“It’s fun,” he says. “I am helping the Global Alliance do whatever it takes to move PA-824 forward. They are using very exciting science and have made tremendous progress on its development.”
Today Baker’s role on the project is to design new analogs and plot the strategy for selecting back-up compounds.
“There is more gold to be mined,” he says, “more promising compounds that can be derived from the PA-824 project.”
Tests to date have demonstrated PA-824’s efficacy through in vitro and animal model assessments conducted at Johns Hopkins University and Colorado State University. Even more promising are in vivo studies that have demonstrated PA-824’s efficacy against replicating Mycobacterium Tuberculosis.
“TB is a huge problem in the developing world,” Baker says. “There will always be a need for new treatments. By leveraging great chemistry and the leadership of the Alliance, we can be a lot more optimistic about getting these to people sooner than expected.”