Hi and welcome to the A16Z podcast. I'm Hannah. In this episode we take a deep dive into the

world of drug development, specifically undruggable drugs, which is a category of protein

or protein family or even a piece of RNA that's so difficult to target

many researchers don't even want to touch it.

Jay Bradner, president of the Novartis Institute for Biomedical Research shares

with A16Z general partners Jorge Konde and

Vijponde and myself all the new tools technologies and breakthroughs which are causing the science

of therapeutics to explode in some of these areas where it's been incredibly difficult or even impossible in the past.

From molecular glues to cell and gene therapies, Bradner shares the behind-the-scenes science stories of what it really takes to make a new drug

that shatters the category of an undrugable target.

So I thought maybe we could start about just talking about what the category of undrugable really

means to the industry. What does that traditionally mean? This is a favorite subject but also for me a

a source subject. The term undrugable refers to as yet the inability to drug a protein or a protein family or a piece of RNA

It's an unfulfilled promise.

Imagine drug hunting with small molecules,

where I've worked and trained,

as sculpting a drug molecule that fits into the pocket of a protein. Well what if there's no pocket?

That protein may be regarded in our discipline as a priori undrugable.

So is it always a shifting kind of category or was there a particular group that always was understood to be that kind of undrugable?

It's very much both. You know, Mars is unwalkable until we arrive there.

Serious human diseases of the non-infectious nature are often caused when pathways go awry.

And these cellular pathways are driven by little machines

...