Fearlessly Forward to our Destination

We are moving rapidly toward escape velocity in our RNA expedition at Arrakis. We want to mark this progress with some updates and perspectives in the Dark Matter blog. In the months ahead, we are rolling out a series of posts called “Fearlessly Forward” to bring you up to speed on how we’ve moved forward in our expedition. (We’ve been called crazy more than a few times, but we think a better word for Arrakeens is fearless.)

For those of you joining us for the first time, it’s worth a quick look back at why we decided to go all-in on the RNA world, why people thought we were crazy, and why we know we’re not.

Our terra firma is small-molecule medicines. We want a drug that we understand, whose behavior is predictable, that is inexpensive and reliable to make, and that can be packed into trucks and shipped to your local drugstore. As we know, small molecules have been the mainstay of our pharmacopeia for several centuries and have, almost without exception, targeted proteins.

We are cognizant of that history and respect it, but we are not bound by it.

Conventional wisdom is that proteins are easier to target than RNA, as proteins are stably and reliably folded into structures with deep and usually functional pockets that are inviting homes for low-molecular-weight compounds. That belief is based on many decades of scientific effort dedicated to deciphering the structure of proteins, including where and how to target them with chemical drugs. As a result, medicinal chemists have developed a powerful toolkit that has made many truly miraculous medicines possible. The pharmaceutical industry has had an amazing run at making small molecule medicines for the 15% of protein targets that are seen as “druggable.” But the remaining 85% represent thousands of prized protein drug targets, proteins whose biology and role in disease is well understood but out of reach of today’s drug discovery toolkit. Perhaps those proteins could be reached by jumping upstream to the mRNA that encodes them. Moreover, there is an even vaster universe of biology contained in non-coding transcripts that can only be reached by directly targeting RNA.

Emerging research, including our own, has pointed the way toward overturning the belief that RNA is an intractable target for small molecules.

Our premise is that RNA is not fundamentally harder, it’s just different. This is why Arrakis set out in 2015 on an expedition to figure out how to develop small molecules that can target RNA. We believed then – and have an even stronger conviction now – that we can use the principles of modern structure-based drug design to create small molecules that bind to RNA.

Let’s explore how we’ve debunked some of the frequently cited obstacles to our mission, and how we’ve cleared the way to keep moving fearlessly forward on our expedition.

Obstacle #1
A fundamental assertion that we heard from the very beginning is that RNA itself is unstructured, lacks well-formed pockets, and as such defies structure-based drug design.

Setting a New Course
At the outset, our intuition told us that it is highly probable that at least some portion of RNA has structure, based on our understanding of thermodynamics and on the empirical reality that small molecule ligands had been found, albeit serendipitously, to bind to RNA targets. Furthermore, the development of new structural biology tools created a wave of published scientific research that began to reveal the secondary and tertiary structures within RNA molecules.

Our Progress
In our work at Arrakis, we have gone beyond showing that RNA structures exist to a new understanding that their structures are, in fact, well defined and canonical – any given RNA has the same folded structure in all cells. Arrakis has built and is continuing to add to a vast and proprietary database of RNA structures determined in living cells that has become an essential part of our platform.

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Obstacle #2
An issue often raised is the undeniable challenge of designing small molecules that can target RNA and achieve an intended effect on the function of that RNA.

Setting a New Course
At Arrakis, we saw the challenges in a different light. For example, whereas RNA’s shape-shifting nature may make it appear challenging to find druggable target sites, its dynamic structure is actually an opportunity, offering many more possibilities to identify rSMs and new small molecule modalities that block the activity of an RNA molecule.

Our Progress
Our team has found multiple avenues for creating bioactive small-molecule ligands for therapeutically relevant RNA targets. We have identified intrinsically-active rSMs that inhibit translation by binding to a well-defined structural motif in RNA in the 5’-untranslated region of an mRNA. In addition, we are creating extrinsically-active rSMs, by endowing our RNA ligands with new functionality, including heterobifunctional molecules that can recruit host effector functions that promote RNA degradation and compounds that block translation by forming a targeted covalent bond on a target RNA. These novel modalities represent just the first of many such inventions as we build a comprehensive toolkit of small molecules that can ultimately target any RNA in the transcriptome.

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Obstacle #3
The methods and tools for protein-targeted small molecules won’t work for RNA, so you have to build an entirely new foundational infrastructure before you can even begin to find drugs to target RNA.

Setting a New Course
RNA lives in our world, so it must obey the laws of physics. But it is nevertheless clear that RNA is playing by a different set of rules. From the start, we envisioned creating a general-purpose end-to-end platform to discover and develop RNA-targeted small molecules. With that goal in mind, we have systematically and relentlessly taken the entire venerable protein-targeted drug discovery toolkit all the way down to the studs and rebuilt it to take aim at RNA targets.

Our Progress
Our platform is now essentially built, with tools and processes that, while recognizable to protein drug-hunters, have been significantly tweaked through hard-learned experience and inventiveness.

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Obstacle #4
Building capabilities on an industrial scale that can create dozens or hundreds of RNA-targeted small molecules is too formidable a task.

Setting a New Course
At Arrakis, we created the blueprint for a comprehensive drug discovery platform, and we have built it brick by brick over the past years. Adding substantially to the resources and ingenuity for this effort, we have attracted two outstanding collaborators – Roche and Amgen – to support our efforts to build a platform that enables us to turn the crank to find small molecules against high-value RNA targets. Our goal on day one – and well in our sights today – is to open the entire transcriptome to small-molecule medicines.

Our Progress
We’ve run over eighty high-throughput screens and have found hits in virtually all of them. Our internal compound library improves with every screen, as we learn about chemical space for RNA. We’ve standardized the process and can screen RNA targets reproducibly on a large scale. Today we can confidently say that we’ve mastered the art and science of RNA synthesis and screening at scale.

Overcoming such obstacles and embracing new mindsets is only possible thanks to the fearless, resilient, brilliant and energized team we have built at Arrakis. The further we travel on this journey, the clearer it becomes that we will get to our destination, sooner rather than later, where we can reliably and systematically design a new class of drugs for a wide range of diseases that will improve the lives of millions of patients.

More coming very soon down the road.