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URL:  https://boards.fool.com/hi-fushi-thanks-for-staying-up-late-and-15297748.aspx

Subject:  Re: ncyte, Lexicon in drug discovery pact Date:  7/3/2001  8:02 AM
Author:  incylong Number:  749 of 803


Hi Fushi, thanks for staying up late and commenting. Let me first comment on small molecules. Note that I said "in the future" (I did not limit it to 10 years, but I would expect it within the next 30 years)

I'm a chemist and was sort of raised on the idea of a small molecule drug as the way to go. However, here are the problems I see.

If we consider non-protein compounds up to about 5000 molecular weight as "small molecule drugs" this probably includes stuff on the market now and in the past and captures biological products hidden away in the rainforst plants etc. There is no reason to believe that for any specific disease/condition there will be an effective (much less safe and affordable) treatment among this group. There is just no logical connection. For 100 years it has been a process of trial and error to find an active agent then systematically modify it to optimize its effectiveness. In the future, if we knew the active site of a protein, then we could probably design a small molecule that would act on it (and God knows what else). Ultimately, we are just designing ligands to biological targets. I suspect that the ratio of potency will be something like this: Effective dose at transcription factor target nM, effective dose at mRNA target uM, effective dose at protein target mM. If you go after a protein you must have a compound that has a million times less effect on transcription factors to avoid possible side effects...etc.

You must determine the structure of the target site in some detail, before you can rationally design a small molecule ligand.

Designing and synthesizing small molecule ligands for known biological targets will be expensive and time consuming. What does that buy you? Maybe you can take the drug orally which has great consumer appeal. To be taken orally, the drug must have stability and physical properties that limit your structural options....You probably cannot really optimize on the biological receptor, you must compromise.

Overall, except for a relative few fortutious cases (most/many of which we already have) there will not be small molecule drugs that are economical to make, highly effective against a specific target, do not interfere with non-target systems (no side effects), and have desirable pharmacodynamics and pharmacokinetics to deliver the effective dose where it is needed.

Proteins (antibodies) are the "natural" way to bind key receptors. The advantage of proteins over "small molecules" is that you can systematicvally synthesize a flock of them and optimize on the target receptor or you can discover the native ligand in vivo and design around that. (You do not even need the protein, all you need is the gene...molecular evolution...AMVE, MAXY, DVSA, PRCS)

The limitation on proteins is delivery (ask PRCS)...how do you get the protein into the cell?

Well as I pointed out, engineering a virus (or naked DNA) to (1) target the specific cells of interest (see ONXX) (2) avoid the immune system (see CRXL), (3) express the protein in the cell is sort of a universal approach..if you can make it work for one protein, you can make it work for many... Suddenly the idea of synthesizing and isolatng and purifying and maintaining protein drugs per se looks unattractive...(in most cases)... let the virus do the delivery and let the cell synthesize the protein de novo.

Well what about antisense. The beauty is that as soon as you know the gene, you know what the drug should look like and you should be able to systematically synthesize via established and routine procedures very quickly and very in expensively. By its nature, the antisense mRNA drugswill be very selective (safe) and the whole process has the potential to be put together in an automated process...punch i the gene code and out pops the antisense drug ...ultimately in minutes...with good confidence that it will work and be safe...undesirable side-effects of suppressing a specific gene can be catelogued.

I see antisense (for down-regulating native genes) and gene therapy (for up-regulating native genes or expressing new genes/proteins) as complementary. There will be niches for protein/antibody drugs (from chicken eggs (GERN etc.), tobacco plants (LSBC), milk (GZTC, PPL)) because they will be available in large quanties very cheaply....without the isses of gene therapy...but selective delivery will be a limiting problem.

I think small molecules will be limited to a few very common products (yes asprin will be around forever), antibiotics and cytotoxins and pro-cytotoxins, hormones, steroids, neuro-transmitters, organoarsenicals (that target zinc-finger proteins), probably some caspase inhibitors, etc.

I keep waiting for the big pharmas to go back through their failed clinical studies (from the last 50 years) to find compounds that worked great in some people, but not in enough to be statistically significant or were too toxic to sub-populations. These drugs would appear to have utility in sub-populations that can now be effeciently identified by DNA analyses (SNPs). This appears to me to be the bigest pool of potential "new" small molecule drugs. I would think we would see a "flood" of compounds that cold be released for use in groups that had been screened by SNP analysis to optimize efficacy and avoid toxicity.

Consider some areas of development: Cancer therapy, I believe the GNTA anti-Bcl-2 antisense drug will greatly enhance the effectiveness of classical chemotherapy (cytotoxic agents) and radioherapy. Exactly the same principle will work on antibiotic resistant bacteria....suppress penicillinase and revive the effectiveness of that well-tested drug.

Then, ONXX (with CRXL technology) will provide a method of systematically purging pre-cancerous clones from people before they are clinically detectable. cancer rates will fall ....so why doe we need all those new fangeled drugs and treatments on the drawing boards at the big pharma's and biotechs?

Of course, we will continue to have B-cell vaccines and VICL will bring us T-cell vaccines.

This is just my humble opinion of course, but I do have about most of my IRA in biotech stocks and none in pharmas. And because I expect protein and small molecule drugs to be with us through my lifetime, I own HGSI, MEDX and PDLI stock as well as most of those mentioned above...not to mention INCY, which depends on the success of the big pharmas...





















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