In conventional medicine, a small molecule, known as a drug, will bind to the protein responsible for disease and, if all goes right, alter the undesirable behavior of that protein. You might remember the “lock-and-key” pictures from high school biology, where the drug is the key and the protein is the lock. The “lock-and-key” concept has grown more complex since coined in 1894, but the basic principle remains: A protein needs a drug that can fit tightly within it. The problem? Up to 85% of proteins in the human body are deemed “undruggable”, according to a recent episode of the podcast “Stereo Chemistry”, produced by Chemical & Engineering News. I was moved by the advances in chemistry, biology, and drug discovery presented on this podcast and am excited to share a summary here.
What makes a protein “undruggable?” A lack of clear pockets, indentations, or other topographic features a small molecule can fit into. According to the podcast, emblematic of an undruggable protein is the protein KRas, which tops people’s lists for what to attack. Why? It is one of the most commonly mutated proteins in cancer.
On the challenges posed by KRas, the podcast interviewed one of my old chemistry professors, Kevan Shokat. (Hi, Professor Shokat!) Professor Shokat talked about how significant it would be to attack KRas with a standard small molecule drug, versus newer forms of medicine, like gene therapy for example, that are not as well understood or as easily executable.
Here are some strategies being used to approach “undruggable” targets:
1. Keep the undruggable protein from ever being made. messenger RNA (mRNA) contains instructions for making proteins, but before doing so, exists in a variety of shapes as the molecule twists and turns. If a target could be designed to “trap” the mRNA in one of these pre-instruction shapes, the mRNA couldn’t go on to direct protein synthesis.
2. Catching transcription factors in action. A transcription factor is a protein that controls the rate of passage of information from DNA to RNA, and thus along to making proteins. They are like regulators of protein synthesis. Sometimes, the transcription factor cMyc becomes stuck in the “on” position, promoting genes that allow cancer cells to multiply. Traditional structural analysis has shown cMyc devoid of any nice pockets to which a small molecule can bind. In the words of Angela Koehler directing the MIT group working on this, the cMyc proteins “lack shape”. However, in the cell when they are working, they do not. Dr. Koehler’s group has found a way to take the proteins as they behave inside the cell and explore them against a library of potential drugs to test for binding. This approach catches the proteins in action, rather than as static structures outside of their typical surroundings.
3. Harnessing the power of mass spectrometry. Unlike conventional approaches, no structural information about a protein is needed beforehand. A protein is thrown in with potential drugs, and the output analyzed by mass spectrometry. Mass spec can determine what stuck on the protein and where. According to Dan Nomura of UC Berkeley, this method has identified 100,000 “druggable hotspots” across 20,000 protein targets. One potential problem: do the druggable hotspots actually influence protein behavior, and therefore, affect disease? That’s where the next idea comes into play.
4. Using the new “druggable hotspots” to simply destroy the protein. If the new hotspot does not affect protein activity, you attach a complex of molecules that will go on to destroy the protein. Once the protein is destroyed, that same complex can perform the task again. This approach is called “Protein Degradation”.
In sum, scientists are taking creative and bold approaches to attacking this huge swath of formerly elusive proteins. I’m excited to see where this goes.