Category Archives: drug discovery


Have any of you ever heard a pharma executive say something like this to their investors:

We ask you to recognize that your investment in our company may not be as profitable to you as it has been historically. At the same time, we ask you to recognize that our scientific efforts serve a fundamental public good, the improvement of human health. We seek to maintain our talented and dedicated workforce because we feel that this human capital is the best way for us to achieve our underlying goal: to provide safe, innovative and life-saving medicines for people that need them. This can only be achieved through a more thorough understanding of what this industry strives to accomplish and we ask you, as investors, to consider what you intend to accomplish through your investment in our company.

I know, I’m a naive schmuck.

Goldmine at NEJM

My previous post led me to peruse the Health Policy and Reform page at NEJM, which I had not seen before. Some very interesting and pertinent data and opinions there. I love this idea from Moses and Martin:

Create a New Class of Bonds
States and the federal government might issue bonds to support innovation in biomedical science and health services, with preference given to high-risk research and diseases important to public health. Such bonds have long been used to support athletic facilities, airports, and roads. They provide a mechanism for private investment to meet public needs.

Potential NIH budget cuts

Surely everyone has seen the news of the new proposal to return NIH budgets to 2008 levels. Calls for those of us in the public sector research enterprise to call or write our Congress Critters are coming from all of our professional organizations right now. If you’re going to call or write your rep, it might be worthwhile to have some numbers in hand to remind that staffer of the impact of NIH research. We all talk about impact on health outcomes, etc., and maybe some of us talk about economic impact of NIH investment but the role of NIH research in private sector development has been harder to pin down (and some of the previous adversarial industry vs. academia spats have not helped). A major argument I have heard from Republicans is that while NIH research is nice and all, the main driver for health care innovation is the private sector. The primary innovation area is widely viewed as pharmaceutical development. This brand spanking new NEJM paper throughs a serious wrench into that argument.

For the too lazy to click crowd, here is a pretty table from the paper:

My favorite part of this, and the argument I am going to use, is that new indications for existing drugs is coming almost entirely from public sector research. There are serious cost savings opportunities to be found going this route and FDA approvals for new indications is just the tip of the iceberg.

Unfortunately for me, my rep, who is almost always responsive to these things, is not able to do the job she has done so terrifically for the past several years right now. I have a feeling, though, that her friends, family and staff can be counted on for strong NIH funding support so I’m gonna ring up the local office.

So much for that

You may remember that not so long ago I wrote about what looked like a drug discovery success story for pain: anti-NGF therapy for osteoarthritis. Well, it looks like that success was short-lived. Somehow I missed this over the Christmas break, but, the FDA has ended trials on anti-NGF therapies for osteoarthritis due to development of avascular necrosis in some patients. Nothing positive can come of avascular necrosis and the pulling of several trials would suggest that this is a drug class effect (or at least suspected to be). Anyway you cut it, this is bad news.

A pain drug discovery success story: anti-NGF therapy for osteoarthritis

ResearchBlogging.orgWith all the recent layoffs in Pharma, coupled with the axing of many analgesic drug development programs within these institutions, its nice to finally see a success (albeit of potentially short longevity — more on that later). The treatment is Tanezumab. Tanezumab is a humanized antibody against nerve growth factor (NGF). The biologic effectively blocks NGF interaction with its receptors, TrkA and p75. Basic researchers in the pain field have been working on the idea of blocking NGF function as a pain treatment for some time now. In fact, I’ve written about this before:

[in response to a question from Whimple] On your other question, are there examples where the clinical never would have been possible without the preclinical the answer is also yes. My example is not a good one because I likely would have been able to instigate a trial but it would have been much more difficult without the preclinical. On the other hand, the anti-NGF treatments for chronic pain are an excellent example of where it would not have been possible. We have known for a long time that NGF is involved in preclinical pain models and in human pain. We have also known that genetic mutations in humans that block NGF signaling (mostly receptor mutations) cause a terrible disease wherein people with the mutation have profound mental retardation, total lack of pain and inability to sweat. While it was the view of most researchers that this was due to a developmental issue, it was not known if blocking NGF signaling later in life would lead to similar deficits and this made any trial on anti-NGF therapies impossible due to very serious safety issues. After decades of preclinical work it is now known that anti-NGF treatments later in life do not cause similar problems and this animal work has made the safety issue a much smaller issue. So, due to literally thousands of papers on NGF signaling in animal models we have a good idea that these treatments will not cause devastating side effects in humans and these therapies are now late in clinical development. If they gain FDA approval I expect that they will become important treatments for chronic pain disorders. That is but one of several examples wherein animal work was absolutely neccessary to develop new pain treatments.

Onto the trial… (Lane et al. 2010 NEJM) The idea was to see if tanezumab would have efficacy for osteoarthritic knee pain. Rather than looking for efficacy in a currently treatable population, the investigators went for the gold and chose to study the effect of tanezumab in advanced osteoarthritis of the knee patients that did not receive pain relief from analgesics (mainly opiates) that are generally used in this patient population. They recruited about 450 patients and broke them into 6 groups: placebo and escalating doses of tanezumab. Treatment was given over 16 weeks and after that time frame they moved to open label. The results are striking: Continue reading

Compare and contrast

From the most recent International Cannabinoid Research Society Meeting Abstract Book: Continue reading

A new mechanism of action for Selective Serotonin Reuptake Inhibitors (SSRIs)?: Pharm 551A, Baudry et al., 2010

ResearchBlogging.orgThis is the last paper for the first section of the class and, as such, it serves as a transition from basic drug discovery work to the next section of the class, the pharmacology of gene expression. The paper, MiR-16 Targets the Serotonin Transporter: A New Facet for Adaptive Responses to Antidepressants, Baudry et al., 2010 Science, is a last minute addition for the class. I had another miRNA and pharmacology paper in this spot before but, when I saw this paper, I couldn’t help myself and switched the papers. Here’s why: Continue reading

Targeting GPCR – Gbeta/gamma with small molecules, Pharm 551A: Bonacci et al., 2006

ResearchBlogging.orgOur understanding of G protein-coupled receptors (GPCRs) has been greatly aided by their relative tractability in terms of pharmacological targeting. These receptors are fairly easy to express in cells and their signaling pathways are amenable to high throughput screening (HTS) technologies. GPCRs couple to a trimeric G-protein structure composed of an alpha subunit and a beta/gamma subunit. The alpha subunit dissociates from beta/gamma upon stimulation of the GPCR and the duration of the alpha subunit signaling is determined by its intrinsic GTPase activity. This GTPase activity can be modulated by regulator of G-protein signaling (RGS) proteins. In terms of GPCR signaling the vast majority of attention has been paid to alpha subunits and part of the reason for this is the availability of molecules (e.g. pertussis and cholera toxins) that target those subunits. Despite this, it is well known that beta/gamma subunits are also capable of generating signaling as these little proteins are known to activate phospholipase C (PLC), PI3Kinase (PI3K) and G-protein receptor kinases (GRKs). Additionally, beta/gamma subunits activate G-protein coupled inwardly rectifying potassium channels (GiRKs) and inhibit certain types of voltage-gated calcium channels (VGCaC). While these signaling mechanisms for beta/gamma are well known, we know relatively little about the physiology of these processes in vivo. This is because we do not have tools to probe the function of beta/gamma pharmacologically. At least not until 2006.

Bonacci et al., Differential targeting of Gbeta/gamma-subunit signaling with small molecules, Science (2006) [free at Science], was the first paper to describe small molecules that target beta/gamma subunits. The first step in discovering these small molecules involved describing a modulatory binding site for beta/gamma function. The authors used phage display of beta/gamma subunits to screen for peptides that bound to these subunits. They discovered a small peptide, SIGK, that bound to a “hotspot” in beta/gamma. They then used this hotspot to screen several thousand molecules computationally for potential binding within this region. They came out of this “virtual screen” with a list of 85 compounds that could then be tested for interference with SIGK binding to beta/gamma. Of these 85 compounds, they found 9 with apparent binding affinity between 0.1 and 60 uM. They then focused on these compounds as potential modulators of beta/gamma signaling.
Continue reading

Agonist-directed trafficking of receptor stimulus, Pharm 551A: Berg et al., 1998

ResearchBlogging.orgAfter doing a whole bunch of cutting-edge papers for the class its time to go back in time a bit (like 1998 is ancient but anyways) and do an oldie-but-goodie. This particular paper, “Effector Pathway-Dependent Relative Efficacy at Serotonin Type 2A and 2C Receptors: Evidence for Agonist-Directed Trafficking of Receptor Stimulus”, Berg et al., 1998 Molecular Pharmacology (Free at Mol Pharm) isn’t really a citation classic (with 278 citations according to google scholar), yet, it marks a very significant moment in GPCR pharmacology. I like this paper for two reasons: 1) It moved a major, emerging pharmacology theoretical framework forward toward experimental discovery and 2) I am very fond of the first and last authors.

First to my fondness for the first and last authors, Kelly Berg and Bill Clarke. Bill and Kelly are professors in the Department of Pharmacology at The University of Texas Health Science Center at San Antonio (UTHSCSA). It so happens that I did my PhD in that very department (I started there in 1998). The very first class I took was Bill Clarke’s Principles of Pharmacology course. When I joined the department I was quite sure I wanted to be a pharmacologist but this course drove that point home for me in ways that are difficult to describe. The course was mainly taught by Bill and Kelly (who happen to be married) with Bill doing most of the teaching on basic principles and Kelly doing the teaching on molecular signaling through GPCRs. While I learned an enormous amount about basic pharmacological principles and the ins-and-outs of GPCR signaling in the class my main memories are of the passion for teaching and graduate education that they both passed on to all of us throughout the semester. I like to think that my teaching style came mostly from the two of them and while I am sure I have not yet lived up to their level of excellence, their example consistently gives me a goal to shoot for. In this class I like to use this paper to transition from screening technologies back to pharmacological principles largely because it reminds me to try to live up to what BIll and Kelly imparted to me through their course.

Okay, enough nostalgia, onto the paper… Continue reading

First step toward the holy grail of pain research? Molecular identity of a mechanically gated ion channel, Coste et al., 2010 Science

ResearchBlogging.orgFor as long as I have been in pain research (and long before I ever even thought about pain research) the topic of mechanically-gated ion channels has been a huge deal. The reasons are simple:
1) We obtain information about our environment through touch (among other things) but in certain conditions touch can become painful. We call this allodynia. The problem is we don’t know how this happens (but we have some good ideas — more on this later) and, ostensibly, identifying ion channels involved in mechanosensation would go a long way toward helping us understand this.
2) Certain types of mechanical inputs are painful (e.g. pinch or pin-prick) and these types of input become even more painful after injury. We call this hyperalgesia and, again, we have some good ideas of the processes that underlie this hyperalgesia but, ultimately, without knowledge of the initial transducer of mechanical inputs, it is hard to understand this fully.
3) Time for the most obvious reason, we just flat out don’t know how we feel mechanical stimulation. There are hundreds (or thousands, depending how you think about it) of papers out there on this but, to date, no one has clearly identified a mechanically-gated channel expressed by vertebrate sensory neurons.

Until now. There were all types of rumors flying around about this at IASP. This is not unusual, however, as I have heard similar rumors at SfN and IASP meetings in the past. On Sept 2, a paper was published in Science from the Patapoutian lab at Scripps, La Jolla, that may open the flood gates in terms of describing how mechanical stimulation is transduced into signals that can be transmitted to the CNS.

How’d they do it? Continue reading