The Game-Changing Potential of Targeting RNA with Small Molecules: More Than Turning the Undruggable to Druggable

Innovation That Matters
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By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx)

Once considered impossible, targeting RNA with small molecules has the potential to be a game-changer. It’s convincing enough to industry veteran Michael Gilman, who essentially came out of “retirement” after he sold Padlock Therapeutics to BMS in 2016, to help start-up Arrakis become the leader in targeting RNA with small molecules. In fact, Gilman committed to be the full-time CEO of the early stage company along with a fresh infusion of capital through the recently-announced $75M Series B investment with round leaders venBio Partners, Nextech Invest, newcomers Omega Funds, HBM Healthcare investments, GV, Alexandria Venture Investments, and WuXi AppTec Venture Fund, and existing investment partners that include Advent Life Sciences, Canaan Partners, Celgene Corporation, Osage University Partners, Pfizer Ventures and the estate of Henri Termeer. The proceeds will be used to support the advancement of the Arrakis pipeline into the clinic, in addition to enabling Arrakis to continue to refine and expand its first-in-industry discovery platform for RNA-targeted small molecules.

What is causing this kind of enthusiasm for targeting RNA with small molecules? We interviewed Michael Gilman to find out.

WuXi: What is the opportunity for targeting RNA in a new way with small molecules?

Gilman: While 85% of the human genome is transcribed into RNA, only a very small portion of those transcribed RNAs (ca. 3%) get translated into proteins. Furthermore, many of those proteins have properties that prevent them from being drugged by small-molecule medicines. So, between these undruggable proteins and all the emerging biology of noncoding RNAs there is a lot of disease biology that remains beyond our reach. By directly targeting RNA, we can bring that biology into play for patients.

WuXi: How has Arrakis built new drug discovery tools to understand how an oligonucleotide like RNA can be targeted with chemically-based small molecules?

Gilman: At Arrakis, we’ve built an end-to-end platform to create small molecules that directly bind to RNA involved in protein expression, impact RNA’s function, and have the potential to treat serious diseases. Wherever possible, we’ve used existing tools. Where there were no tools, we built new ones.

WuXi: You are focused on oncology as one of the first therapeutic areas for Arrakis’ pipeline. Can you describe how RNA-targeted small molecules address oncology in a new way?

Gilman: Targeting RNA with small molecules offers a fresh approach to tackling non-druggable proteins that have been known for a long time are critically involved in cancer – such as MYC, RAS, and other classic oncogenes and transcription factors. I was a post-doc in Bob Weinberg’s lab at the Whitehead Institute in the mid 80s, when the roles of MYC and RAS in human cancer were discovered. Yet despite all that we have learned, we still do not have drugs against RAS and MYC 35 years later. On top of that, recent work has revealed additional critical driver genes in cancer, synthetic lethal genes, and key vulnerabilities in the host immune system. All of these targets are in play with RNA.

WuXi: What are other areas, beyond oncology, where you are developing Arrakis’ pipeline?

Gilman: In addition to building a pipeline for oncology, Arrakis is developing small molecule medicines to select genetically and clinically validated targets for diseases in other therapeutic areas.

WuXi: Can you describe in greater detail how Arrakis has built the range of tools required to target RNA with small molecules?

Gilman: Over the past two years or so, we’ve used our Series A funding to build our platform for discovering RNA-targeted small molecules. The first thing we had to do was to rethink the paradigm and understand exactly what problems we had to solve. Some of these challenges are quite similar to protein-targeted drug discovery, so we could leverage decades of invention and refinement in the protein world. But other challenges are unique to RNA, in particular, inferring structure and function from primary sequence. This required new tools, especially computational methods. In between these extremes were a variety of standard drug discovery methods that had to be thoroughly retooled to work with RNA.

WuXi: In total, what does the Arrakis platform encompass and what does it achieve in drug discovery and development?

Gilman: The proprietary platform we have built at Arrakis enables the systematic discovery and design of RNA-targeted small molecules, integrates leading‐edge RNA bioinformatics and chemical biology tools, RNA‐specific chemical and biological assays, and RNA-directed medicinal chemistry. By leveraging the best existing tools along with Arrakis’ exclusive technologies, Arrakis can identify small molecules that modulate RNA function and predictably impact important biology in disease processes.

WuXi: Can you describe how you now use the Arrakis platform, and some of the unique steps that are involved in the drug discovery process for RNA-targeted small molecules?

Gilman: Let me break it down into three key aspects as to how we now systematically discover and develop RNA-targeted small molecules (rSM)

First, we have learned how to predict and experimentally validate RNA structure and locate drug-friendly pockets in these structures. Second, we have extensively modified multiple small-molecule screening platforms to make them work with RNA. Third, with the hits we’ve obtained from these screens, which are delightfully druglike, potent, and selective, we’ve begun to learn the rules of small-molecule SAR for RNA. Many of those rules are quite similar to proteins, but some are astonishingly different.

WuXi: Can you offer a big picture perspective on what it’s been like to make these accomplishments in a new areas of drug discovery?

Gilman: When we started two years ago, most investors we talked to thought we were out of our minds to be doing this.

Some would say “No way you are going to be able to do this because RNA is not well structured, it’s floppy, and there’s insufficient sequence variation (only four building blocks compared to twenty in proteins) to achieve the molecular selectivity required for drug development, or even if we succeeded at finding molecules, they’d be too weird.” It turns out that none of those presumptions are true.

Now that we’ve shown that we are routinely obtaining high-quality chemistry against high-value targets, Arrakis is poised for its next phase of growth and development, building a pipeline and a next-generation biopharma company.

WuXi: As a small company can you comment on your external strategy?

Gilman: Like many startups these days, externalized research with partners is critically important to our progress. We’ve had terrific experiences with WuXi in screening your libraries, performing synthetic chemistry, and running cell-based assays.

WuXi: What do you wish to accomplish over the next few years at Arrakis?

Gilman: As the company continues to evolve, Arrakis is focusing on building a compelling pipeline, a vertically integrated organization for the development of our own powerful new medicines, with additional programs in the hands of various global partners.

We have come a long way in a relatively short period of time. Targeting RNA with small molecules has the potential to be transformative and opens up the opportunities to make the undruggable druggable.”

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