In the video game Pac Man, players move a chomping mouth to gobble up invaders. Our bodies use a similar approach to get rid of unwanted cancer cells—protein molecules called proteases chop up developing cancer cells. Unfortunately, crafty cancer cells have figured out ways to neutralize Pac Man by producing high levels of protease inhibitors, called IAPs. When Drs. John Reed and Guy Salvesen began studying these molecules, they already knew that IAP levels were elevated in certain cancers and helped cancer cells survive—they just didn’t know how. Their seminal studies demonstrated that IAPs directly bind to and neutralize proteases, explaining how cancer cells survive.
The next step was to find drug candidates that dislodge IAPs from cell death proteases, thus restoring the natural mechanism to dispose of cancer cells. Based on the 3D structure of an IAP, solved by Drs. Guy Salvesen, Stefan Riedl and Robert Liddington, Dr. Reed’s team successfully pioneered these cancer drug discovery efforts, creating the first method for IAP drug screening and identifying active inhibitors. Several IAP inhibitors are now in clinical trials.
An IAP-inhibited caspase
An active caspase