Making Kinase Inhibitor drugs more effective

Kinase inhibitors block kinase enzymes from ‘phosphorylating’ your healthy messages; while more than 30 drugs now exist, nature provides many compounds that can effectively do the same job; but this is a very complex subject. 

Kinase enzymes cause phosphorylation 

‘Kinase Inhibitors’ are a new class of drugs that inhibit an enzyme (a protein kinase) which causes phosphorylation of important proteins. By adding a phosphate group to cellular proteins the protein kinase causes the recipient protein to change its performance. This can lead to illnesses including cancer. Hence scientists had the idea to block the kinase enzymes from making the changes. This occurs in nature. Many natural compounds possess the ability to block protein kinases.

It has even been calculated that there are 555 known natural protein kinases that can affect messages from the Human Genome in the human body and create havoc.

The phosphate groups are usually added to the amino acids serine, threonine, or tyrosine. Some kinases cause phosphorylation by attacking tyrosine, most attack both serine and threonine jointly. Phosphorylation is involved in disease because it changes the recipient from its healthy functioning state (1).  Protein kinases and phosphorylation play a huge role in several diseases, such as cancer, neurodegenerative diseases, microbial infections, and inflammation

Many protein kinases are found on the surface of the cell. The first kinase inhibitor was a tyrosine kinase inhibitor, Gleevec (Immatinib) in 2001. More than 30 have been launched since (2).

Types of Kinase Inhibitors

There are many targets for KIs, for example:

1. Some Kinase Inhibitors are target specific, 

   1. For example - EGFR inhibitors - Cetuximab, Erlotinib, Gefitinib

   2. For example - MEK inhibitors - Cobimetinib,  

   3. For example - BRAF inhibitors - Vemurafenib

   4. For example - VEGF inhibitors - Pegaptanib, Lenvatinib

   5. For example - FGFR inhibitors - Erdafitinib

2. Others may have several specific targets - Afatinib (EGFR/ErbB2); Dacomitinib (EGFR/ErbB2/ErbB4), Vandetanib (RET/VEGFR/EGFR)

3. Others have multiple targets - Sorafenib, Sunitinib

Kinase inhibitors and epigenetics

Oncologists frequently talk about ‘mutation’. “You have a BRAF mutation” someone with colorectal cancer or melanoma might be told. This is technically incorrect. The word ‘mutation’ actually means a sequence change inside the DNA. About 7% of people inherit such a mutation, for example BRCA1/2. But with BRAF, EGFR, MEK, VEGF and the others, we are not talking about permanent rearrangement of the coding inside your DNA, just the addition of a phosphate group to one of your messages making it work imperfectly. Theoretically such changes are ‘epi-genetic’ (in other words, they occur outside the genome), and the copying process (from DNA to RNA to a protein message) has gone wrong. Why? From a build up of pollution inside the cell. This was all explained by Christine Mayr of Sloan Kettering, whose work won her the prestigious NIH Pioneer award - See ‘Cancer - why you’re not doomed’.

Phosphorylation is the perfect example of epi-genetic change - message change taking place in the microenvironment of the cell. Clearly scientist think this is potentially reversible. ‘Block the kinase enzymes from doing their worst!’ That’s the plan. But don’t you think the defence systems would be in place in our bodies anyway?

Significant Side-effects with Kinase Inhibitors

And here’s the first problem. We were told repeatedly that the newer more tightly targeted drugs would bring less side-effects with them. Far from it. Wikipedia (2) has a chart listing all the Kinase Inhibitors to date; some of the side-effects (depending on the drug) are horrendous - Kidney failure, liver damage, GI tract damage and perforation, gallbladder damage, lung disease and of course neuropathy and cardiovascular failure. 

Natural Kinase inhibitors

Because of the significant side-effects associated with synthetic drugs, it is not surprising that researchers have studied natural compounds as alternatives (3).

Indeed, there is an incredible amount of research on natural kinase inhibitors largely because 

   i) there are so many (555) protein kinases in a cell; and despite  their dangers, humans have thrived; and 

   ii) drug companies look at what works in nature when they start to build synthetic drugs based on their findings..

The review from a team in Poland is excellent and if you go to the reference you will be amazed at just how much research there is on Natural Compounds as Kinase Inhibitors.

Unsurprisingly, the essence of the colourful Mediterranean Diet  - polyphenols and flavonoids - provide a great number of potential Kinase Inhibitors. 

For example, from the Rainbow Diet:

* Turmeric inhibits IKKß (5), it inhibits MEK (6), tyrosine kinase and JAK (7)... and many more kinases!  

* Resveratrol - directly inhibits mTOR, multiple pathways and kinases (8).

* Genistein is a known EGFR tyrosine kinase inhibitor (9)

* Quercetin acts on multiple kinase inhibitor targets (10)

* Caffeic acid  - in fruits, vegetables, wine, olive oil, and coffee (11)

* Milk Thistle - A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signalling and induces cyclin-dependent kinase inhibitors in prostate cancer (12). 

* Herbs such as Oregano, Rosemary, Sage have each been shown to act as Tyrosine Kinase Inhibitors (13).

* Cucurbitacin - in more bitter cucumbers is a potent Tyrosine kinase inhibitor (14).

We will let the Chinese have a winner too - 

* Honokiol (from the magnolia bush) inhibits the PI3K/Akt/mTOR pathway and regulates EGFR expression and phosphorylation. Also inhibits the activation of the mTOR pathway and downregulates CDK2 and CDK4 (4) 

Cancer stem Cells T-cells and more

The effects of Kinase disruption doesn’t stop with an imperfect message. Many of these messages cause higher levels of cancer stem cells at the heart of the tumour; others can disrupt the immune system through cytokine or T-cell inhibition.

Understanding pathways

And here’s the biggest problem. While I could only find one natural compound (Dandelion) that had research showing it could clash with Kinase Inhibitor drugs, many of the natural compounds - just like their drug counterparts - are kinase specific. If you use a compound like Genistein, while it won’t cause a problem, research tells us that it is of no benefit on non-tyrosine Kinase disrupted pathways. 

Frankly, you would need a Biochemist with a lot of time on his or her hands to sort this out for you. If you have any expertise in science you could simply start with the Polish review (3).  Or you could just start with a Search engine such as Brave or Google, and put in your personal pathway (BRAF, MEK, etc) which you can obtain from your Doctor or histology, and put each of, say,10 natural compounds with it, starting with the list above, and see what lights up. This is not for amateurs. While you are unlikely to cause harm, you could waste a lot of money.

Go to: Epigenetics and Reversing cancer

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References

1. Protein Kinase Inhibitors - NCI - https://pubmed.ncbi.nlm.nih.gov/31643906/ 
2. Wikipedia - https://en.wikipedia.org/wiki/Protein_kinase_inhibitor 
3. Compounds from Natural Sources as Protein Kinase Inhibitors; Andrea Baier, Ryszard Szyszka; Biomolecules 2020 Nov; 12:10(11) 1546
4.  Ong C.P., Lee W.L., Tang Y.Q., Yap W.H. Honokiol: A Review of Its Anticancer Potential and Mechanisms. Cancers. 2020;
5. Turmeric Ingredient Inhibits Kinase in Cancer Pathway; https://www.onclive.com/view/turmeric-ingredient-inhibits-kinase-in-cancer-pathway 
6. Turmeric, the MEK inhibitor - https://pubmed.ncbi.nlm.nih.gov/31675556/ 
7. Turmeric; Tyrosine Kinase, Jak inhibitor -  https://www.sciencedirect.com/science/article/pii/S0223523419306361 
8. Resveratrol inhibits mTOR - https://www.nature.com/articles/srep21772/ 
9. Genistein: An Integrative Overview of Its Mode of Action, Pharmacological Properties, and Health Benefits; https://www.hindawi.com/journals/omcl/2021/3268136/
10. Quercetin inhibits a large panel of kinases implicated in cancer cell biology; https://pubmed.ncbi.nlm.nih.gov/21206969/  
11. Caffeic acid, a phenolic phytochemical in coffee, directly inhibits Fyn kinase activity - https://pubmed.ncbi.nlm.nih.gov/19073879/ 
12. Milk Thistle, Professionals, OncoLink -  NCI
13. Rosemary - Natural Products as important tyrosine Kinase Inhibitors - https://www.sciencedirect.com/science/article/abs/pii/S0223523419308086 
14. Cucurbitacins as potential anticancer agents: new insights on molecular mechanisms; Translational Medicine,31  December 2022

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