KRAS Cancer Drugs Explained: How KRAS Became a Drug Target

In this discussion, Asfar S. Azmi, professor at Karmanos Cancer Institute Comprehensive Cancer Center and Wayne State University, explains how advances in structural biology and drug development transformed KRAS from an “undruggable” target into one of the most important areas in cancer research.

KRAS was long considered one of the most elusive targets in cancer. While scientists understood its role in driving cancer, it was not seen as druggable because most successful drug targets have deep binding pockets where drugs can attach. KRAS, however, has a unique structure. It is more circular, like a golf ball, with shallow ridges and no obvious deep pockets for drug binding.

That structural limitation made it extremely difficult to target for many years. Researchers eventually began studying KRAS more closely and discovered that it cycles between an on and off state. When KRAS is on, it promotes cancer growth. When it is off, it does not. In most patients with a KRAS mutation, the protein remains stuck in the on state.

Scientists then observed that during the transition between the on and off states, a temporary opening appears in the protein. That insight became a key breakthrough, allowing researchers to design drugs that bind during that window and interfere with KRAS activity.

Since that discovery, research has expanded further. New approaches are now targeting not only the off state but also other conformations, including the on state itself. This has led to the development of multiple new therapies.

Overall, Azmi highlights that deeper structural understanding of KRAS, combined with advances in technology and drug design, opened the door to targeting a protein once thought impossible to drug.

Transcript

What changed in our understanding that finally made KRAS a druggable target?

This was one of the central targets and a very elusive target in cancer. We knew a lot about KRAS, but it was never considered a druggable protein. The reason is that most proteins used as drug targets usually have deep pockets that drugs can bind to. KRAS had a unique structure. It is very circular, like a golf ball, with shallow ridges, and there were no deep pockets for drugs to bind.

That was a major challenge. But researchers began to look more closely at the structure. What they found is that KRAS turns on and off. When it is turned on, it promotes cancer. When it is turned off, it stops cancer. In most patients with a KRAS mutation, the protein stays on.

What chemists noticed is that when KRAS transitions between the off and on state, there is an opening. That opening was targeted using drugs, and that became the first step in targeting KRAS. Since then, more work has been done. Now there are new approaches where not only the off state of KRAS is being targeted, but also other states, including the on state.

Many different drugs have emerged through a deeper understanding of the structure and the discovery of pockets that were previously undiscovered. All of this was made possible by advances in technology and emerging science that helped drive drug development.

Transcript edited for clarity an conciseness

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