How Spicy Would You Like That Chemotherapy?

Molecules are abstract objects, so it’s easy to talk about one using the single property we know about it. Penicillin cures infections. Chlorophyll harvests sunlight. Cocaine gets you high. Thinking this way keeps everything simple and makes it easy to tell a story about them. Referring to molecules by a single characteristic keeps things simple.

Unfortunately, nature hates simplicity.

A molecule doesn’t know the role we’ve given it. It wiggles blindly through solution, crashing into others. It only knows the other molecules and particles it directly interacts with. It percieves nothing about the upstream or downstream effects it has on a cell, an organism, or the environment.

If a molecule finds a site where it can stably rest, it will stay there a while, often triggering nearby molecules to change as a result. These changes can in turn drive other changes of nearby molecules, and cascade along to generate the local effect of that molecule. In this interaction, both the molecule and the environment are important. Change the environment, and a molecule can have dramatically different effects. Compounds that plants use as insecticides give us an energetic buzz, or work as effective painkillers. Likewise, small changes in a molecule can dramatically change the activity of that molecule in the same environment.

So, both the molecule itself and the surrounding ones can influence the ultimate effect. Changing either can bring about completely new interactions and behaviours, with different consequences. While loyalty of molecules to a single function would make them easier to talk and think about, most of them are philanderers.

Molecules are Promiscuous

We want molecules to behave in a simple way that makes sense. We want them to be monogamous and true to a single role. Finding non-promiscuous drugs is one of the big challenges of pharmaceutical development. We need a molecule to be effective at the desired location, without interacting anywhere else. When we use a compound, we want it to be specific to its desired function and not interact with any others. Dirty drugs are rarely good ones.

We get side effects when drug molecules interact with other proteins, cells, or tissues than they were developed for. An effective nervous system drug isn’t very useful if it kills kidney cells. Unfortunately, off-target binding is the norm, rather than the exception. Compounds that exert the desired effect in one place can drive very negative effects elsewhere.

On the flip side, there are many molecules that have safely entered clinical trials to treat disease, but aren’t very good for their intended use. These relatively safe drugs can sometimes be directed toward different functions, to treat other conditions. This is known as drug repurposing. A number of effective medicines have emerged this way. Exploiting the promiscuity of compounds can help us find new uses for old drugs.

Of Chili Spice and Cancer

It’s often interesting when a molecule breaks the predefined role we’ve given to it and shows us a completely different function. For instance, a compound once evaluated for its ability to reduce high blood pressure instead inhibits antibiotic resistance enzymes. Sildenafil, a drug once tested for pulmonary hypertension, had an unexpected and lucrative side effect. A puzzling and exciting compound, rapamycin, has both antibiotic and immune suppressive effects, while also appearing to extend the lifespan of healthy mice.*

I thought of this kind of molecular versatility when I came across a paper in ACS Chemical Biology: Phosphorylation of Capsaicinoid Derivatives Provides Highly Potent and Selective Inhibitors of the Transcription Factor STAT5b. This headline means that a molecule from chili peppers can be modified to block to a protein involved in cancer progression. Out of context, this seems bananas. How would a molecule similar to hot pepper spice be used to fight cancer?

The protein targeted in this study is required for the progression of certain forms of cancer. Inhibiting its action using a small molecule drug could halt the growth of cancer in its tracks. A previously discovered inhibitor contained a group with two phosphates attached, and they decided to apply the same modification to another molecule that has the same base structure – dihydrocapsaicin. This molecule one of the main compounds responsible for the spice of hot peppers. As far as I can tell, it was chosen because it was a commonly available natural chemical that could undergo the same modifications as the previously discovered inhibitor, and possibly act the same way on the protein.

Upon testing, the modified chili spice molecule did exactly that – it blocked the protein. But why?

Burn, baby, burn!
A molecular mimic from an unconventional source

A Wolf in Phosphotyrosine Clothing

A look at the structure of the inhibitor compound provides a clue. It looks a lot like a familiar modified amino acid: phosphotyrosine. Tyrosine is one of the 20 amino acids that make up proteins. Addition of a phosphate group turns it into phosphotyrosine. Our cells use enzymes that switch it between these two forms to regulate the activity proteins.

The STAT (Signal Transducer and Activator of Transcription) transcription factors are regulated by tyrosine phosphorylation. These proteins contain tyrosines that can be phosphorylated by kinase enzymes. They also contain protein modules that tightly bind to phosphotyrosine. As a result, a pair of phosphorylated STAT molecules form a mutual handshake, gripping their phosphorylated twin tightly. Once this pair forms, the protein is able to carry out its function, turning on genes involved in cell growth and division.

Adding a molecule that binds in the place of phosphotyrosine keeps the molecule from being efficiently phosphorylated itself, and also blocks it from binding to a phosphorylated partner. This stops the activity of the protein, which is needed for the continued growth of cancer cells. By blocking the activation of STAT molecule, the progress of a cancer cell can be stopped. Small molecules that mimic phosphotyrosine could in turn be effective anti-cancer drugs.

Exploiting Molecular Promiscuity

The site that capsaicin normally binds, the ion channel TRPV1, is nothing like the STAT proteins. Completely unrelated. So, the interaction of modified capsaicin to STAT is completely independent of its role in food. Capsaicin and its derivatives may share some characteristics that help it perform both roles, but those roles are completely indepdendent.

Add some chili flakes to your curry and you trigger a hot and/or pain response. Make a couple chemical changes and inject into a tumour, you could now use a similar compound as a chemotherapy compound. And that’s just two characteristics a molecule could have. With thousands of genes in the human genome, there are countless potential targets a molecule could bind, for better and for worse. It takes smart planning and study to figure out what’s possible.

This is an interesting case of what the researchers call “semi-rational design” of a chemical compound. Taking chemicals that already exist in nature, making changes to make them look more like drugs for a specific target, they identified a new specific inhibitor of a protein. The goal is to take complicated natural molecules, through a simple transformation, convert them into more effective chemicals for the desired function. In this way, it’s possible to leverage nature’s huge diversity of chemical compounds, and tailor them to get the function we want from them.

Breaking the Mold of Molecular Function

This paper shows us that a molecule is not destined for a single role. Small changes can dramatically alter its effect. In addition, directing a molecule to a different target will result in a completely new function. There is an enormous diversity of compounds we can pull from in the lab, and in nature. If we’re smart, there are probably ready solutions out there for us to go and find.

Will this compound revolutionize the treatment of cancer? Unlikely. Will eating a spicy diet help fight the disease? Certainly not, at least not by this mechanism.

The lesson I take from this work is that we shouldn’t be too quick to brand a chemical based on a single characteristic and dismiss any of the other functions it could have. Context, environment, and chemical properties are always relevant when we discuss the action of a chemical.

*Rapamycin is a compound surrounded by extraordinary claims (and hype). There’s not enough space to go into it today, but hopefully I can talk about it in the future.


Elumalai N, Berg A, Rubner S, & Berg T (2015). Phosphorylation of Capsaicinoid Derivatives Provides Highly Potent and Selective Inhibitors of the Transcription Factor STAT5b. ACS chemical biology PMID: 26469307



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