Targeting the RNA Lifecycle

At Arrakis, we pursue the far-reaching therapeutic opportunities presented by RNA biology.

Emerging research, including our own, has answered fundamental questions about the RNA lifecycle, providing a glimpse into the two- and three-dimensional structures that RNA forms to control these processes and the broader lifecycle of the cell. Since our launch in 2017, Arrakis has accumulated deep knowledge across the lifecycle of RNA and we have built tools to intentionally target steps in the process using small molecules that predictably impact biology.

It is now possible to overturn the conventional belief that RNA is intractable as a small molecule target. The most established drug modality, small molecules, can now target RNA and dramatically expand the realm of RNA-targeted medicines beyond the limits of oligonucleotide drugs. This new wave of RNA-targeted small molecules (rSMs) is created by applying well-understood principles of bioinformatics, medicinal chemistry, computational chemistry, structural biology, and molecular and cellular biology to make RNA a therapeutic target addressable by small molecules.

Identifying drug intervention points across the RNA lifecycle

Central to our approach is an appreciation of the richness of RNA and the links between its sequence, structure and function. In particular, we now know:

  • RNA folds into predictable and often conserved secondary and tertiary substructures that can be inferred from sequence.
  • RNA substructures are functionally significant, influencing steps in the RNA lifecycle such as splicing, translational efficiency, and degradation.
  • Synthetic RNA structures can be demonstrated to match the structures within cells.
  • RNA structures are diverse and dynamic, and selectivity is achievable with small molecules.

These RNA properties allow us to deploy the principles of conventional, protein structure-based drug design to establish a drug discovery workflow for RNA and design RNA-targeted small molecules (rSMs) to treat disease. 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 sequence-structure-function relationships and RNA-small molecule interactions that enable us to select the most promising target/hit combinations to advance as therapeutic programs.

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