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  • Hi, my name is Jim Wells. I'm with the departments of Pharmaceutical Chemistry

  • and Cellular and Molecular Pharmacology at UCSF.

  • And I'm going to tell you today about the process of drug discovery and development

  • in two parts: part one it will be screening of compounds and in that regard I'll be joined by my colleague

  • Michelle Arkin.

  • Hi, I'm going to talk after Jim gives an early history of drug discovery

  • and talks a little bit about target identification, then I'll talk about the process of screening

  • and hit identification.

  • Great, see you in a bit.

  • This slide shows some of the products of modern drug discoveries,

  • such as Lipitor, which is used for cholesterol lowering,

  • or a more recent drug, Gleevec, which an anti-cancer drug.

  • These compounds were discovered through a very rational, systematic

  • process, involves a lot of exciting scientific discoveries

  • as well as a lot of serendipity, luck and hard work.

  • To understand how we found these compounds, it's useful for us to review

  • how drug discovery came to be,

  • what's the sort of brief history of drug discovery, as I'll show you on the following slide.

  • To understand the modern drug discovery development process today

  • it's useful to review the history, briefly,

  • of drug discovery. Prior to 1900, most drugs, in fact only a few really,

  • were identified through human screening.

  • Natural products, for instance, aspirin, was discovered from tree bark.

  • Quinine was discovered. And even illicit drugs like cocaine were discovered.

  • Long about the turn of the century, 1906,

  • the Food and Drug Administration was established

  • because a number of these kinds of potions or elixirs were found to neither be safe nor efficacious

  • and it was necessary to regulate these in a systematic way.

  • And this led to the development of animal based screening, for example, to discover anesthetics,

  • bacterial screening to identify antibiotics, and the like,

  • tissue screening to identify compounds that could react with neurological receptors,

  • like GPCRs, HTS, high throughput screening,

  • now very common discovery technology, as you'll hear a lot more about in this talk,

  • for discovering target-based compounds.

  • And then, lastly, mechanism-based discovery, which was used for HIV drugs and the like

  • as well as molecular and cellular based screening for kinase inhibitors.

  • And finally, genomics, to actually profile patients to determine who will be affected and who won't be affected.

  • So, in fact, this process, the history of drug discovery,

  • had gone from the human to the molecular target

  • and this now in reverse reflects what we actually do today.

  • Shown on this slide is what, in sort of general terms,

  • the modern drug discovery process.

  • And this process starts off with a disease,

  • and from that disease one tries to, through a lot of biochemical

  • cell-based, genetic and other means identify

  • what is the target or the molecular species in a cell, in an organism,

  • that's causing that disease.

  • One then develops a drug to that target, as you can see here,

  • and then, having identified that target, one then needs to identify

  • a compound that will interact with that target in a phase called lead discovery.

  • This is a chemical process where we identify the first compounds

  • that are actually important in modifying a disease

  • and then once compounds are identified, typically in cells and then in animals,

  • they're prepared for clinical trials in this process called drug development,

  • which is, this phase is really about interfacing the compounds that we discovered here

  • to the human biology that we wish to effect here.

  • And if successful, we'll come out of this process with a drug.

  • Now, this process is a long winded process. It typically takes about now about 10-15 years

  • to discover a drug and it's expensive too.

  • It's about half a billion to a billion dollars to develop a drug.

  • So, when you're thinking about the pills that you take in a bottle,

  • think about a shopping mall, because that's easily the cost that it takes to get to the drugs that we end up using.

  • Ok, I wanted to just review quickly what kind of classes, what kind of molecules constitute drugs.

  • There's actually three basic classes and they include

  • the small molecule, organic compounds,

  • typically, these are compounds whose molecular weight is less than five hundred

  • and they're taken, generally, orally,

  • although they can also be taken as an injectable.

  • And they represent the kind of classic drug that you think of when you go to a pharmacy,

  • that you would buy over the counter, for example.

  • There's another class of very important drugs known as the protein therapeutic drugs.

  • These are typically injectable drugs, molecular weights of over ten thousand,

  • often up to a hundred thousand, or even higher.

  • And they are the important class of biotherapeutics

  • and they represent about thirty percent of drug sales today.

  • The other class of drugs, actually one of the very first to be developed

  • are the vaccines. And these are

  • basically viruses, pieces of viruses, that are used to elicit an immune response to a disease.

  • So these are the basic categories and today I'm going to focus on small molecule drug discovery,

  • leaving these other two categories alone for another talk.

  • So, the process of small molecule discovery is a long and winding road.

  • And it starts off with identifying what is the most critical target that's involved

  • in mediating the disease. So, identifying the disease target.

  • Having identified that target, generally a protein target,

  • one then goes through a process known as hit identification, shown here,

  • and the role of hit identification is to get the first compounds that actually engage the target.

  • Which compounds actually bind to the protein of interest

  • and can begin our drug discovery process.

  • From there, taking that isolated protein in a test tube, we need to show that that compound

  • actually works in a cell.

  • And so, this begins this process called hit to lead

  • which is to generate a compound which has cellular potency.

  • The next stage, sort of drawing from there, to a larger scale,

  • is the lead optimization stage.

  • This is a critical stage in which one actually shows that these compounds

  • that have been generated have animal efficacy and actually work in a pharmacological model

  • for the disease. The next stage after that is the IND enabling stage,

  • this is the stage that is preparing compounds for clinical trials.

  • Primarily, it involves animal tox experiments, in addition, chemical synthesis, scale,

  • and formulations experiments, and at the end of this process, one would hope to have a package

  • that you could convince the food and drug administration that you have a compound

  • that is going to be both safe and efficacious when administered to humans.

  • Then begins the all-important human clinical trials

  • if the FDA agrees with you.

  • In the first trail, is for human safety. This is typically done in a dose escalation,

  • kind of trial, with healthy volunteers, although in certain disease settings, like cancer,

  • you can use people with cancer.

  • And the goal of this is really to find out

  • what is the circulatory lifetime of the drug in humans

  • and how safe is the drug if its dose is increased.

  • The next phase, phase two, is involved in determining the efficacy of the drug

  • in a disease setting. So, this would be taking patients with the disease,

  • treating them with your drug at a level that's below any toxicity that was observed in phase one

  • and in ranging doses to find out what is the efficacy of the drug as a function of its dose

  • and what's the best dose to best effect the disease.

  • So, from these small trials, then, one then moves into a much larger, what's called registration trial,

  • phase three, in which one then fixes the dose, fixes the disease,

  • fixes the formulation, and then treats a large number of cohorts, both with and without the drug

  • to determine how effective the drug is. And at the end of this time, if your drug is safe and efficacious, you'll submit

  • what's known as a new drug application, an NDA,

  • to the FDA. They will either, they will review it and agree with you or not,

  • that you have a drug that's ready to go into humans

  • and at the end of that process, you have this pill down here,

  • which will then be launched with great fanfare, because this process is, as you'll see, a very long and arduous one.

  • Ok so I'm going to start at the beginning here with target ID.

  • What's causing the disease? How is it, what is the actual molecular target that we want to go after?

  • This link to the disease of interest.

  • And this is actually a very, very, can be a very long process

  • to find out what causing the disease.

  • Many diseases we don't have a clue as to what their cause is.

  • And in fact, ironically, even with all the tests that we might do to validate a target,

  • the final validation of a target is not known until you get down here with the pill itself,

  • to see if that is actually effective in a human.

  • Ok, so just briefly, what are the general causes of disease, what are the things that we think about.

  • First thing is, I like to think is it a bug or is it in the body?

  • Is it an infectious agent

  • or is it a host imbalance? So, for instance, if it's an infectious agent,

  • that's causing the disease, generally these days, we have sequences of the pathogenic bacteria.

  • We'll find a target that's not in humans

  • and then we'll take that protein target and go after that

  • in the drug discovery process.

  • If however, it's a disease like host imbalance, maybe it's a metabolic disease or cardiovascular disease or cancer

  • you first have to decide is it due, is the disease caused by an underactive protein,

  • for instance, people with diabetes,

  • they're not as responsive to insulin and so by giving them back insulin

  • you can hope to modify and ameliorate that condition.

  • Other diseases, for instance, here, many cancers are caused by overactive proteins

  • such as kinases, and so there's a lot of interest in discovering drugs

  • that would inhibit specific kinases for cancer.

  • Ok, that is just sort of a very skimmed view of this process, but just to give you a sense.

  • Once you have identified the target, this target process actually can be very complex.

  • So, the human genome is vast, there's some twenty thousand genes

  • that code for proteins. And finding exactly which one is causing the disease

  • can be challenging. So, one you've come up with the protein,

  • and the gene that encodes it for that particular disease,

  • you're ready to go on to another very important consideration.

  • Which is that not only do you need to go after the biology of the target,

  • the target itself, which is causing the disease, but that target is

  • itself has to be amenable to small molecule discovery.