[Nescafe]

Hi,

I was reading about the cell cycle and the abnormalities associated with cancer and noticed that often the target for drugs is the tyrosine kinase receptors that very much so initiate the signal transduction pathway. I get that it is better to target upstream stream tyrosine kinase instead of lets say cyclins for example because even if we inhibit cyclins in the nucleus the tyrosine kinase is still active and can just signal for more cyclins. But would it not be more specific to target a protein such as cyclin which is very much the gate keeper for cell growth and division?

My other question is, I understand cell permeability and the complications involved with getting passed the cell membrane but what about the nucleus. What are the complications involved in getting through it? do drugs just make their way to the cytoplasm and only get by to the nucleus if they are super small?

To summarize my confusion, first, why target upstream and not downstream, second, how can we design a drug that gets into the nucleus?



Nescafe.

[fledarmus]

Both upstream and downstream targets are used, based on the indication and on other effects. Both have their pros and cons. The choice of which particular structure to target for any disease or indication is based on a wide range of factors. I can give you a few contrasting examples:

1. In some cases, in mechanisms that are carefully controlled by the body, the production of the downstream targets is rapidly increased in response to the presence of an inhibitor. To be effective at reducing the activity of the downstream target, you would have to add enough of the inhibitor not only to block the enzyme that is present, but also to overwhelm the body's ability to upregulate the target. In these cases, you may be able to get by with much lower doses of drug by blocking the upstream target and preventing the production of the downstream target in the first place, rather than by trying to block the effect of the downstream target.

2. Protein-protein signaling interactions are notoriously hard to block with small molecule inhibitors, and the experimental systems for determining whether your molecule will inhibit the interactions are difficult to set up. Enzymes, which catalyze specific chemical processes, are much easier to block and much easier to study outside the body. So if your downstream target that you would really like to block is a signalling protein, it may be much easier to develop molecules that block some enzyme further up in the process that produces the signalling protein rather than to interact with the protein itself.

Of course, one of the problems with blocking the upstream targets is that they may be involved in more than one biochemical pathway, and blocking the one that leads to the disease state may also block one that is necessary for normal functioning. In these cases, you may see fewer side effects going directly for the downstream targets.