Thursday, May 9, 2013

Researchers discover a new class of FGFR inhibitors

Fishing new drugs

Currently, one of the most used strategies to discover new potential drugs is one called high throughput screening (HTS). This is a technique by which the researcher is able to test thousands of compounds in a very short timeframe, allowing finding those which have best/more affinity with a specific target. In other words, researchers are fishing new potential drugs attracting them by using specific baits (could be for instance the fibroblast growth factor receptor type 3, FGFR3). Another way to see this practice is to think it is a kind of filter. You put the grounded coffee in the filter, add hot water and your cup will be filled only with the rich and tasty dark liquid.

Many of the new generation of anticancer drugs available today were discovered using HTS and the researchers keep using this technique to find more. That’s how the new potential drug of the title of this article has been identified. We will be briefly reviewing how can this new drug could point to a new strategy against the mutated FGFR3 and see if it could be used in achondroplasia.

The tyrosine kinase inhibitors (TKI) and how they work

Currently, many of the new TKIs used in the treatment of cancer, such as imatinib, dovitinib (also known as TKI-258, a pan-FGFR inhibitor), work by blocking a specific region within the tyrosine kinase domain of the target receptor enzyme called ATP pocket.

Let’s translate this hard jargon sentence in something meaningful. This previous article of the blog describes the TKI mode of action (it includes a link to an animation showing how the TKIs work) but, in short, these inhibitor compounds are like an electric outlet cover (figure).

When one such agent binds to the ATP pocket, it prevents the electrical charging of the tyrosine (an amino acid, part of the structure of the enzyme), which in turn prevents the binding and activation of neighbor enzymes. This is what we call enzymatic cascade or pathway, where an activated enzyme activates the next one and so on, like in a domino chain (we reviewed this here). When you cover the outlet nobody can plug in a blender or a coffee maker, could they?

Cancer cells use enzymes like FGFR3 to stimulate the cell nucleus to keep multiplying. These enzymes trigger cascades that accelerate cell duplication (proliferation) and slow the cell natural death process (apoptosis). So, you see why there is so much investment in this area. If you block the stimulators, the cancer loses the ability to progress and can be more easily (if so) combated.

We have also previously mentioned that proteins (enzymes) may have several distinct actions depending on their amino acid sequence and structural conformation. Regions such as the ATP pockets are considered natural active sites within the enzyme. Drugs that act on these active sites are described has having an orthosteric mode of action (from the Greek, meaning right place, in free interpretation). However, not all drugs act directly by this orthosteric way of working. They can also interfere in the enzyme activity in other places along its structure. When this occurs, researchers classify these drugs as having an allosteric mode of action (from the Greek, meaning other place, in free interpretation; this link to Wikipedia gives a nice explanation about this topic). In this context, as mentioned above, classical TKIs work blocking the ATP pockets, natural active sites of receptor enzymes, so they have an orthosteric mode of action.

You might remember that FGFRs have three regions, also called domains:

  • extracellular;
  • transmembrane;
  • intracellular (or tyrosine kinase)

Part of the receptor enzyme is located outside the cell, working like a chemical antenna. There is a transmembrane part, which crosses the cell wall and is the place where, in the FGFR3, the achondroplasia mutation is located (figure).

And, finally, there is the intracellular domain, where the ATP pockets are located, the part responsible for turning on the chemical cascade we are often mentioning in the articles of this blog. Thus, for a TKI to exert its actions, it must enter the cell.


Recently, Bono F et al. and Herbert C et al. (1,2) published a pair of studies in which they were looking for candidates for new potential drugs to block receptor tyrosine kinases (RTKs). Surprisingly, during their analyses they found that one of the molecules, although not having a special affinity to the receptor (the bait, remember, they were fishing), was capable to reduce the receptor activity.

Testing this compound further, which they called SSR128129E, they discovered that it works by interacting with the receptor outside the cell, in an allosteric fashion. This two patterns: working outside the cell and allosteric mode of action make this new compound a first representative of a new class of receptor enzyme inhibitors, as interpreted in an editorial note of the journal Cancer Discovery. (3)

In the case of SSR128129E, one of its characteristics is that it does not block FGFR activity completely, just reduce it, which is a very interesting property. We must remember that both over activity and zero activity of a protein might cause problems to the appropriate functioning of a cell. In the case of FGFR3, over activity leads to bone growth impairment (as seen in achondroplasia) and no FGFR3 might also bring health problems in animal models and in humans. (4,5) If we could reduce significantly the action of an overactive FGFR3, this could be sufficient to rescue normal or near normal bone growth.

The second positive finding is about its site of action. Since it works outside the cell, it wouldn’t have to cross the cell membrane, one of the natural barriers for any intracellular acting drug.

The third positive property is that it seems to be very specific for FGFRs, not reacting to the other cell wall receptors. This is very, very important, since one of the challenges of the classical TKIs is that they are not specific enough against FGFRs (or particularly FGFR3) to allow their use in achondroplasia (the case of TKI-258 and other several FGFR inhibitors we have already listed in previous articles of the blog).

A fourth positive insight is that, traditionally, allosteric inhibitors (or modulators, another way to name them) tend to produce less toxicity than the classical orthosteric drugs.

Straight to the point: is this an option for achondroplasia?

The researchers were looking for new inhibitors of FGFRs and the molecule they found is a pan-FGFR inhibitor. This means that it works against all four recognized FGFRs due to their strong homology (they are quite similar in terms of structure). From a first sight, it would not be suitable for use in growing organisms, as they naturally rely on proper chemical functioning of these receptors. However, before just blindly saying no, this could be the case of testing it in an achondroplasia-like cell culture model. The investigators tested SSR128129E in several cancer models and the response was positive. No matter if this particular compound couldn’t be used in achondroplasia, the discovery of this new drug class opens a door to explore more specific molecules, which is an interesting perspective.

  • the first compound of a new class of FGFR inhibitors has been described;
  • it works in all four FGFRs outside the cell, in an allosteric fashion;
  • it doesn’t block completely FGFR activity
  • it works in cancer cells bearing over expression or over activity of FGFRs.

Days ago another study dealing with a strategy wich we have already discussed here was tested successfully against another receptor enzyme. We will explore this study in the next article, always having in mind potential correlations with FGFR3 and achondroplasia.


1. Bono F et al. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF Receptor blocker with allosteric properties. Cancer Cell 2013;23:477–88.

2. Herbert C et al. Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling. Cancer Cell 2013;23:489-501.

3. Research Watch: Targeted therapy. A first-in-class FGFR Inhibitor suppresses tumor growth Cancer Discovery. Published online first April 25, 2013; doi:10.1158/2159-8290.CD-RW2013-088.

4. Colvin JS et al. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genetics 1996;12:390-7. doi:10.1038/ng0496-390.

5. Toydemir RM et al. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am J Human Genet 2006;79(5):935–41.

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