The era of rational drug design begins…

In a previous post I talked about barn doors and picking locks: how we need to get far more specific and selective in recognizing how to kill only cancer cells and leaving normal cells intact. Let me continue the lock and key analogy just a little bit further.

Suppose you found an old trunk in the basement or in the attic and it was secured by a huge padlock and you had no idea where to find the key. You could search through every key in your pocket or on your key ring, you could look in that little junk drawer in the kitchen that we all have or you could ask all of your neighbours to bring their keys to see if any of them might fit the lock. But that would be like kissing thousands of frogs in the hope of finding one Prince!

That might be great for children's fairy tales, but it isn't what a logical, thinking person would do. I’ll bet you’d call a locksmith who would be able to design a new key for the lock and get you into your trunk. (Actually, you might be prone to get a pair of large bolt-cutters and destroy the lock, but play along with me for the sake of the mind experiment!)

A few years ago anew drug called Gleevec hit the market and was the embodiment of this lock and key analogy. Gleevec was a drug that was targeted at a particular kind of cancer, a leukemia called chronic myelogenous leukemia or CML.

We had known for a long time that CML was characterized by an abnormal chromosome fusion. A small piece of chromosome 9 gets fused to a piece of chromosome 22 and creates a new DNA sequence at the point of fusion that does not exist in normal cells. It just so happens that this new DNA sequence encodes a new protein that is comprised of two pieces of two proteins that normally never see one another. A small part of a gene called BCR from chromosome 22 gets fused with a gene called ABL on chromosome 9. It is the over-expression of this new hybrid protein, not surprisingly called BCR-ABL, that creates the cancerous condition.

If you think of this new hybrid protein as a lock, then think of Gleevec as a specific key that fits into this lock and actually shuts the activity of the protein off. The abnormal protein is effectively stuck in the “on” position, and Gleevec interacts with a critical part of the protein and basically turns it into more of an “off” position. When the new abnormal proteins is no longer abundantly produced, the cancer effectively goes away…

The diagram below shows a schematic of this process. The green “ribbon” is a 2-dimensional approximation of what the CML abnormal protein looks like and the small molecule in red(Gleevec) is shown in the critical pocket of the protein where it interacts to turn it from “on” to “off”.

From a patient’s perspective, what is even more remarkable is that this new drug, that works so specifically, actually comes in a simple capsule. Take a pill, cure a cancer. How elegant is that?

That all sound good in theory. Does it really work?

Well there are countless patients alive today who will tell you that it does. Take Mr. Jason Blake, for example. Many of you will remember Jason Blake as a star hockey player for the Toronto Maple Leafs. Blake was diagnosed with CML a few years ago and was treated with Gleevec. By most accounts of the day, he barely missed any games and continues to play today, now with the Anaheim Mighty Ducks. In January 2010 when he was traded from Toronto to Anaheim, he was naturally asked about his cancer. According to an article in the L.A. Times on January 31, 2010, he said “"It's basically forgotten about now. I take a pill as someone would a vitamin every day...   At the end of the day, I never think about it. It doesn't affect me.“

Pretty hard to ask for a better outcome than that!

But realize that this kind of success of so called “rational drug design” or designing a key to fit a lock, ONLY can happen if you know what the lock looks like in the first place. No more kissing thousand of frogs, but you HAVE to understand at the molecular level what is the specific mutation or mutations that are the root cause of the cancer, and then isolate or design a specific drug that targets that/those mutation(s).

This is why we are beginning an era of trying to catalogue as many cancer-causing mutations as we can, in as exquisite and fine detail as possible, and why the era of “precision medicine” or more “personalized medicine” is firmly upon us.

More about that to come...