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I was reading an article on a recent identification of a PARP-14 protein in cancer cells that is responsible for production of additional glucose which keeps cancer cells from dying, and that a PARP-14 inhibiting drug is still a long way from becoming reality.

Would like to ask any medical researchers/anyone with adequate knowledge, what is the difficulty in producing drugs that inhibit production by a certain protein? Isn't it about analyzing the chemical makeup and structure of the protein and finding ways to neutralize it? As how other types of drugs are made? Please give some specific examples regarding this topic. Your help is much appreciated.

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  • $\begingroup$ Can you please link to or cite the article? $\endgroup$ – canadianer Sep 27 '15 at 4:18
  • $\begingroup$ Basically the problem is finding or designing compound that can either competitively bind to the active site of a protein or an allosteric regulatory site that does not also interfere with proteins necessary to maintain cells elsewhere in the body. $\endgroup$ – AMR Sep 27 '15 at 4:20
  • $\begingroup$ @canadianer I am not sure that the link to the article is necessary. The OP gives a specific example and then asks a more general question about developing chemotherapeutics that target proteins, not necessarily why it would be difficult to find one for PARP-14. No? $\endgroup$ – AMR Sep 27 '15 at 4:25
  • $\begingroup$ @AMR It's not necessary, but I'd like to read it. $\endgroup$ – canadianer Sep 27 '15 at 4:27
  • $\begingroup$ @canadianer ncbi.nlm.nih.gov/pubmed?LinkName=gene_pubmed&from_uid=54625 Sounds like it makes some form of modification to histones in DNA damaged cells that rescues them and contributes to their survival. $\endgroup$ – AMR Sep 27 '15 at 4:32
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Drug production is very long, tedious and costly process. It generally takes more than 10 years to make entirely new drug. It has various iterative aspects. take a look at following cartoon showing various steps in drug design ( Taken from Anderson 2003 )

enter image description here

Now coming to your questions,

what is the difficulty in producing drugs that inhibit production by a certain protein?

First of all you need to know other effects of that protein which might be essential for normal cell function. For example, there are many genes overexpression patterns which have correlated with cancer. This suggest excess quantity of these proteins/factors leads to cancer. Now one would like to block these proteins with inhibitors. However if you block these proteins, they might also affect regular cellular function. For example, SHC1 overexpression is correlated with breast cancer. However that protein is very important in apoptosis regulation, EGFR pathway, Oxidative stress and many more functions. Now if you inhibit this protein, your normal cells will also get damaged.

Isn't it about analyzing the chemical makeup and structure of the protein and finding ways to neutralize it

It is not that simple, for this you need inhibitor which can specifically either bind (it can be competition also) specifically with given protein. Most of the time there are other problems like , there might be other proteins with that structure which can affect other protein's function. There will be other important problems like

  • Delivery of inhibitor
  • Specificity (Inhibitor need to act only on target cells)
  • Sensitivity (Inhibitor need to be sensitive enough to get full response in low concentration)
  • Side effects (There might be side effects of this inhibitor which should be minimized)
  • Cell resistance (Many times cell becomes resistant to inhibitor)

Above mentioned points are actually major issues in all cancer treatments like Chemotherapy , Radiation therapy, Immunotherapy , Hormone therapy etc.

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  • $\begingroup$ Nice, but whether the protein is important for normal cell function was not part of the question I think. One thing is to figure out how to specifically inhibit a given protein with a drug (which is hard enough in itself). Whether this is a good idea at all, given the various functions the protein might have in the body, is a separate problem. $\endgroup$ – Roland Sep 27 '15 at 14:07

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