字幕列表 影片播放 列印英文字幕 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. And by that I mean it has to be something that we think could bind a small molecule.