Arrakis is on a path to bring powerful new RNA-targeted small molecule (rSM) therapies to millions of patients.

RNA as a Therapeutic Target

The potential therapeutic value of targeting RNA is well recognized. But to date, intentionally targeting RNA has required oligonucleotide drugs, which have challenging pharmaceutical properties that limit their utility for patients. Nevertheless, there are precedents for RNA-targeted small molecules (rSMs), including several approved drugs. In contrast to oligonucleotide drugs, these molecules were all discovered through serendipity; only after their discovery was it learned they acted on RNA.

Emerging research has answered fundamental questions about the complex lifecycle of RNA and its suitability as a target for structure-based small molecule drug discovery. No longer thought to be an inconsequential intermediary between DNA and proteins, we now know:

  • RNA folds into predictable and conserved secondary and tertiary structures that can be inferred from sequence
  • The in vitro structures can be demonstrated to match the structures within cells
  • RNA structures are diverse and dynamic, but selectivity is achievable with small molecules
  • RNA structures are functionally significant, specifically influencing the translational efficiency of the RNA into protein

These RNA properties allow us to deploy the principles of structure-based drug design so we may rearchitect the drug discovery workflow for RNA and design disease-treating rSMs. We are screening hundreds of RNA targets to deeply explore chemical and RNA structure space. The result is a unique understanding of the principles of RNA-small molecule interactions and the ability to select the most promising target/hit combinations to advance as therapeutic programs.

RNA pockets and dynamics
The pockets and dynamics of RNA provide multiple opportunities to intervene in the life of an RNA to alter its function. RNA folds into complex three-dimensional pockets that can be characterized computationally and experimentally. These pockets are remarkably similar to druggable pockets in proteins. In addition, RNAs interconvert into multiple related conformations that can each be targeted by small molecules to impede RNA function.

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