Cancer cells don’t die

cer cells differ from healthy cells in several ways, but the key difference is their ability to avoid death. All cells in the body are programmed to self-destruct at pre-determined times—when they get old, when their function is compromised or when they are no longer needed. This function is short-circuited in cancer cells, and without the ability to die, they continue to grow uncontrolled. This resistance to death was a well-known hallmark of cancer cells.

If scientist could find a treatment that targeted proteins known to be important in the apoptotic process, they might be able to reset the cell-death process and induce cancer cell death. As the researchers knew, several proteins are part of the apoptotic process, and while some of these proteins prevent cell death, others trigger it. These proteins communicate with each other in a complex system. At the time, most believed these proteins were too difficult to target with small-molecule medicines, leading many to consider them “undruggable” targets.

Discovery towards  Bcl-xL

A technology called SAR by NMR (structure-activity relationships by nuclear magnetic resonance), which uses NMR spectroscopy—a way of measuring the interactions between molecules using radio waves—to identify very small organic molecules, or fragments, that bound weakly to the target protein.

When those fragments that bound to Bcl-xL were identified, scientists again used NMR spectroscopy to gather structural information on how the fragments were binding to the protein. They could then use chemistry to link these weak binders together, producing a larger molecule which bound tighter to the Bcl-xL protein.

After the discovery of the first potent inhibitor of Bcl-xL, the journey to a drug was still far from over. What followed were years of dedication and more groundbreaking research in structural biology, medicinal chemistry, pharmacology and development sciences to produce a medicine.