Targeting the Transcriptome with Small Molecules

The transcriptome encompasses all of the RNA transcribed from our genetic blueprint, including coding RNAs—which are translated into proteins—and noncoding RNAs—which regulate the fate and function of coding RNA and proteins. There are over 200,000 RNA transcripts—a vast pool of potential therapeutic targets. In contrast, today’s medicines address approximately 500 protein targets of a small number of structural classes derived from among 20,000 coding genes. New insights into the dynamic structure and diverse function of RNA point to new opportunities for targeting RNA with small-molecule compounds. Arrakis is pioneering the discovery of medicines that focus on a new class of targets—RNA.

The biological importance of RNA, and especially the potential value of targeting RNA therapeutically, has been well recognized. But to date, intentionally targeting RNA has required oligonucleotide drugs which have challenging pharmaceutical properties that have limited their utility for patients. Nevertheless, there are several precedents for conventional small molecules that bind and modulate RNA activity, including several approved drugs. In contrast to oligonucleotide drugs, these molecules were all discovered serendipitously; only after their discovery was it learned that they acted on RNA.

Arrakis is opening the human transcriptome to discover a new class of small-molecule medicines that treat diseases that are beyond the reach of today’s medicines.

Arrakis is pursuing a very different approach to RNA targets by intentionally designing small-molecule inhibitors of RNA function. New research demonstrates that most RNAs, like proteins, fold into characteristic two- and three-dimensional structures, creating binding pockets that make the discovery and design of selective and potent RNA-targeted small molecules feasible. The pharmaceutical industry has invested billions of dollars over several decades to develop tools and techniques to create drugs for protein targets. Adopting the vast armamentarium of techniques and knowledge gained in successfully targeting proteins, Arrakis is re-architecting drug discovery to build a proprietary industrial-scale platform to discover and develop RNA-targeted drugs with the advantageous pharmaceutical properties of small-molecule medicines, including oral administration, biodistribution, and cell penetration.

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