The Pill That Could

Chapter 4: The Compound

In a small laboratory at Oregon Health Sciences University, on a winter morning in 1995, Brian Druker is counting colonies in petri dishes.

There are two stacks of dishes on the bench in front of him. Each dish contains a thin layer of soft agar — a clear, jelly-like medium — with cells suspended in it. The cells, when they're healthy and dividing, multiply over the course of a week or so into small, dense balls of cells called colonies. You can see the colonies under a low-power microscope. You can count them. The number of colonies in a dish tells you how many of the cells you started with were able to grow.

The dishes in the first stack contain cells from a patient with CML. The dishes in the second stack contain bone marrow cells from a healthy donor — normal cells, the controls. Each stack is split into two groups: dishes treated with a small molecule that arrived several months earlier in a glass vial from Switzerland, and dishes treated with the same volume of the same buffer but no small molecule.

Druker counts the untreated CML dishes. Lots of colonies, as expected; the leukemia cells grow well in soft agar. He counts the treated CML dishes. The colonies are gone. There are a few stragglers, but the difference is unmissable: the dishes that received the small molecule have lost essentially all of their CML colonies.

He counts the untreated normal dishes. A reasonable number of colonies. He counts the treated normal dishes. Almost the same number of colonies. The drug, whatever it is, is not bothering normal bone marrow cells.

He counts everything again, slowly, because you don't get to see this kind of result very often, and when you do, you check it.

* * *

Before going any further, it's worth being clear about what kind of object this small molecule is, and why making it had taken seven years and a small company's worth of effort.

A kinase, as we established in the last chapter, is an enzyme that attaches a phosphate group onto a specific spot on a target protein. A kinase inhibitor is a small molecule that prevents the kinase from doing this. The way most kinase inhibitors work is by occupying the spot where the kinase normally puts the phosphate — not the spot on the target protein, but the spot on the kinase itself, where the kinase grabs the phosphate from in the first place.

Where does the kinase get the phosphate from? It gets it from a small molecule called ATP — adenosine triphosphate, the universal energy currency of every cell in every organism on earth. ATP is, structurally, a sort of three-part molecule: a base, a sugar, and a chain of three phosphate groups attached to the sugar in a row. The bond between the second and third phosphate is somewhat unstable; breaking it releases a useful amount of energy, which the cell can apply to whatever job it needs done. Most of what cells do, in the way of work, is powered by breaking that bond. A kinase, in the act of phosphorylating its target protein, breaks the bond by transferring the third phosphate from ATP onto the target. The kinase is, in effect, a tiny machine that takes ATP, takes a target protein, and combines them so that the phosphate ends up where it should.

To do this the kinase has, somewhere in its three-dimensional structure, a pocket shaped to hold ATP. The pocket is roughly the same shape from kinase to kinase, because ATP is the same shape in every kinase. The pocket has a few specific contact points where particular parts of the ATP molecule fit snugly. Detailed-features-wise, the pocket varies a little: a particular kinase has a slightly different lining, in places, from the next kinase. But the overall geometry is conserved, because they all have to bind the same fuel.

A kinase inhibitor that works by occupying the ATP pocket is, in essence, a small molecule shaped well enough like ATP that the pocket accepts it, but unable to do ATP's job once it's in there. With the inhibitor stuck in the pocket, the kinase can't load real ATP, and so can't transfer a phosphate. The enzyme is, for as long as the inhibitor is bound, switched off.

This is, in principle, an attractive way to drug a kinase. ATP is small — small enough that the molecules that compete with it are small too, and small molecules tend to be the kind of compounds that can be made into pills, get absorbed through the gut, distribute around the body, and reach their targets. The trouble — the reason this approach had been failing for years before Druker's package arrived from Switzerland — is selectivity. There are, as the prologue mentioned, more than five hundred kinases in the human genome. They all have an ATP pocket. The pockets vary, but not by a lot. A molecule that fits the ATP pocket of one kinase very often fits the ATP pockets of many others. And since the body needs many of those kinases doing their jobs in order to keep functioning, a molecule that hits all of them is not a drug, it's a poison.

The challenge, in 1990, was making a molecule that exploited the small differences between kinase ATP pockets to bind one kinase tightly while leaving the others alone. Drug chemists had been trying for years. The general view was that selectivity at the level required — hitting a single kinase out of five hundred, with no significant effect on the other 499 — was probably not achievable. The kinases were just too similar. Every time someone made a compound that worked nicely on one kinase, follow-up testing would reveal that it also worked on a dozen others. You could kind of hit a kinase. You couldn't selectively hit one.

All 13 chapters of The Pill That Could · Library · All courses