RNA: Opening New Doors in Medicinal Chemistry, a Special Issue

Over the past several years, the pharmaceutical industry has increased its efforts to identify novel drug targets outside of the usual mantle of G protein-coupled receptors, ion channels, and enzymes of multiple families, including kinases, in order to provide a greater variety of therapeutic options for patient populations across a number of disease states. In this context, recent attention has turned to looking for regulators of RNA function, including small molecules and biologics.

Previously considered “difficult to drug” on a structural and selectivity basis, considerable efforts in academia and industry are now being focused on targeting RNA as a therapeutic modality. These efforts are driven based on both the biological significance of RNAs, as well as a growing number of studies implicating aberrant RNA biology in many human diseases.¹⁻⁷ In cells, RNA molecules are essential for cellular information transfer and gene regulation; however, it is now known that, beyond serving as a link between DNA and proteins, RNAs can also play direct effector roles by binding to various ligands, including proteins, DNA, other RNAs, and metabolites. In this manner, RNAs mediate cellular processes such as the regulation of gene transcription, splicing and the enhancement or inhibition of protein activity. Not surprisingly, based on the myriad important functions of cellular RNAs, their dysregulation is often associated with disease phenotypes and RNA molecules are increasingly recognized as potential targets for drug development efforts.⁸⁻¹¹ As we will see in this Special Issue, small-molecule- and oligonucleotide-based therapies are being pursued toward the goal of targeting RNA biology. This broad range of approaches, which also includes the targeting of RNAs and RNA-binding proteins and RNA-modifying enzymes, is in line with the known complexity of RNA biology and regulation. Our hope is that this Special Issue will bring attention to the breadth of RNA-targeted drug discovery and highlight contemporary approaches for taming this “undruggable” class of biomolecules.

To begin, Guest Editor Amanda Garner provides a broad overview of challenges and advances in this topic area in an Introduction.¹² Subsequently, Hasane Ratni and colleagues at Roche discuss the discovery of risdiplam, the first FDA approved small molecule splicing modifier drug.^13,14 The discovery of small molecule splicing modifiers and the development of risdiplam for the treatment of spinal muscular atrophy (SMA) have now firmly established proof-of-concept for targeting RNA with small molecules and transformed a scientific curiosity into a viable technology to target disease. Following on the success of risdiplam and branaplam, which is under development for the same indication,¹⁵ efforts to discover novel small molecule splicing modulators continue. Skyhawk Therapeutics has recently disclosed several new scaffolds with such activity, and these patents are highlighted by Ram Sabnis.¹⁶⁻²¹

Although it is now recognized that many RNAs can adopt complex tertiary structures akin to proteins,²² classically, RNA has been targeted in a sequence-based manner rather than structure-based manner. Antisense oligonucleotides (ASOs) remain a powerful class of biologics for targeting RNA based on sequence.^23,24 Thazha Prakash and colleagues from Ionis Pharmaceuticals describe a new chemical strategy for improving the therapeutic index of ASOs,²⁵ which adds to the wealth of chemical technologies for enabling this field and has great potential for aiding the development of treatments for many human diseases.

While biologic approaches continue to play an impactful and ever-growing role in RNA-targeted drug discovery, considerable efforts are now being devoted toward the targeting of RNAs with small molecules. In the issue, both a diversity of RNA types, as well as strategies for small molecule discovery, are highlighted. Contributions from the laboratories of Matt Disney at Scripps Florida and Steve Zimmerman at the University of Illinois at Urbana–Champaign describe new approaches for developing small molecule ligands for expanded repeat RNAs causative in the neurodegenerative disease myotonic dystrophy.²⁶ The targeting of another family of noncoding RNAs, microRNAs, is also covered. A paper from the laboratory of Maria Duca from the Université Côte d’Azur describes a continuation of their efforts toward the rational design of aminoglycoside conjugates for targeting microRNA-21 (miR-21).²⁷ A collaborative contribution from the laboratories of Amanda Garner and Ashootosh Tripathi at the University of Michigan also focuses on targeting miR-21.²⁸ Using screening technology developed by the Garner group,^29,30 the team now discloses the discovery of natural product inhibitors of microRNA maturation. Recent work from Matt Disney in developing fragment-based approaches for RNA-targeted discovery is also included as a patent highlight from Ram Sabnis.³¹ Relevant to microRNAs, this strategy has been recently reported by the Disney lab for the discovery of selective inhibitors of miR-21.³²

Aside from traditional biochemical screening methods, interest in computational screening approaches for RNA targets is also growing.^33,34 This arena of RNA-targeted drug discovery is also represented. May Khanna’s group from the University of Arizona describes an in silico screening strategy for targeting the long noncoding RNA, MALAT1.³⁵ Additionally, Aaron Frank’s lab from the University of Michigan reports a computational approach for mining for ligandable sites in RNAs using HIV-1 TAR RNA as a model.

In addition to targeting RNAs with small molecules, RNA-binding proteins and RNA-modifying enzymes are also emerging as new therapeutic modalities.^36,37 Contributions from the laboratories of Peng Wu and Jordan Meier provide new insights into these areas of RNA-targeted drug discovery. The Wu lab from the Max Planck Institute reports a new class of small molecule inhibitors of Lin28 providing new chemical matter for developing antagonists of its interaction with the microRNA, let-7.³⁸ The Meier lab from the National Cancer Institute describes a valuable study aimed at evaluating a putative chemical probe targeting the RNA acetyltransferase NAT10.³⁹ Through their careful studies, they demonstrate that remodelin should not be used as a specific inhibitor of NAT10, providing useful data for researchers in the field.

Overall, this issue highlights the diversity of science in the broad field of RNA-targeted drug discovery. It is our hope that, through the research reported within the issue, members of our medicinal chemistry community will learn more about this field, inspiring the development of new ideas for tackling this last frontier in drug discovery.

Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.