This report provides you with a landscape description and analysis of discovery and development of small molecules against RNA as a drug target from an industry perspective as of September 2019.
The report brings you up-to-date with information about and analysis of
Since 2017, nearly US$ 1 bln has been raised by start-up companies targeting RNA with small molecules in financing rounds and from partnering deals. This huge amount of money highlights the tremendous interest from investors and major pharmaceutical companies and the opportunities they recognize in these new approaches to target RNA with small molecules.
Nearly all small molecule-based drugs in clinical use target proteins. It is estimated that about 20,000 human proteins are expressed by the human genome and 10-15% are thought to be disease-related. However, many of them are considered as undruggable for various reasons, e.g. because they lack a distinctive motif for small molecule binding.
Originally thought to be merely a conduit for moving information encoded in the nuclear genome to the protein translational machinery in the cytoplasm via the canonical DNA-RNA-protein pathway, RNA is now increasingly known to have multiple roles, both coding and non-coding and to take myriad forms. Besides messenger RNAs (mRNAs) which encode proteins, and the ribosomal RNAs (rRNAs) involved in translating them, understanding continues to grow of the multitude of non-coding RNA (ncRNA) molecules, such as microRNA (miRNA), piwiRNA, long non-coding RNA (lncRNA), antisense RNA, short hairpin RNA and circular RNA. About 75% of the human genome is transcribed into RNA, yet only 1-2% encodes proteins.
The recent advancement in the knowledge about diversity, structural and functional information related to RNAs has put them in the lime light as a drug target. RNA has an important role in the transcription regulation, regulation of the translation, catalysis, protein function, protein transport, peptide bond formation and RNA splicing. New findings have identified RNA as a potential target in multitude of diseases including bacterial/viral infections and cancer. Just like proteins, RNAs can form well-defined tertiary structures, such as double helices, hairpins, bulges, and pseudo-knots.
With the ability to target RNA, the potential pool of drug targets would dramatically expand.
Strong proof-of-principle for RNA-targeted drugs has been provided by antisense oligonucleotides and synthetic RNAs that e.g. redirect the cellular RNA interference (RNAi) machinery. In addition to antisense and RNAi, which includes short interfering RNA (siRNA) and miRNA, other RNA therapeutics include mRNA, self-amplifying mRNA (samMRNA) and small activating RNA (saRNA).
However, nucleic acid-based therapeutic approaches involve large, often highly charged molecules with the associated delivery challenges, e.g. they do not pass the blood-brain barrier to to reach the brain or spinal cord, and have some toxicity issues (e.g. platelet count).
Another strategy to target RNA involves using small molecules as modulators of RNA. Small molecules are one of the most recent emerging RNA-focused therapeutics. They have several advantages over RNA molecules, including oral administration, easier entry into cells and better stability.
Several approaches are pursued to target RNA with small molecules:
mRNA Translation Regulation: Regulation of gene expression at the level of mRNA translation is a fundamental mechanism for moderating cellular events. The translation of single specific mRNAs, subsets, or even a majority of the mRNAs in a cell, is controlled almost exclusively through a multitude of interactions that occur between RNA-binding proteins and regulatory elements embedded throughout the mRNA.
RNA Splicing Modification; Post-transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic cells by which an RNA primary transcript is chemically altered following transcription from a gene to produce a mature, functional RNA molecule that can then leave the nucleus and perform any of a variety of different functions in the cell. Three major steps significantly modify the chemical structure of the RNA molecule: the addition of a 5' cap, the addition of a 3' polyadenylated tail, and RNA splicing.
Direct RNA Targeting: RNA can form complex three-dimensional structures through canonical Watson-Crick base pairing and complex tertiary interactions that are mediated by non-canonical bonds. Such structures can be as intricate and stable as those formed by proteins and can recognize small-molecule ligands, other nucleic acids, or proteins with high affinity and specificity. Modern molecular techniques provide in-depth insides to the RNA structure and function. X-ray crystallography, nuclear magnetic resonance, and cryo-electron microscopy yielded a solid foundation for understanding the chemical and structural basis of RNA functions at atomic resolution. The development of RNA-centric deep-sequencing probing techniques opened up the possibility for the global assessment of RNA structures at a single nucleotide resolution, and in various biological contexts.
Indirect RNA Targeting – Epitranscriptomics: The epitranscriptome includes all the biochemical modifications of the RNA (= the transcriptome) within a cell. Epitranscriptomics involves all functionally relevant changes to the transcriptome that do not involve a change in the ribonucleotide sequence. Thus, RNAs are indirectly targeted via the proteins they interact with.
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Table of Contents
1 Executive Summary
2 Introduction & Overview
3 mRNA Translation Regulation by Small Molecules
3.1.2 Technologies and Targets
3.1.3 Preclinical and Clinical Experience
3.1.4 Partnering and Financing
3.1.5 Comparative Assessment
3.2 Company Profiles
3.2.1 Anima Biotech
3.2.2 eFFECTOR Therapeutics
3.2.3 Eloxx Pharmaceuticals
3.3. Selected Technology Profile
3.3.1 Translation Control Therapeutics Platform
3.4 Drug and Drug Candidate Profiles
3.4.1 BAY 1143269
3.4.3 eIF4E Inhibitors
4 RNA Splicing Modification by Small Molecules
4.1.2 Technologies and Targets
4.1.3 Preclinical and Clinical Experience
4.1.4 Partnering and Financing
4.1.5 Comparative Assessment
4.2 Company Profiles
4.2.1 H3 Biomedicine
4.2.2 Panorama Medicine
4.2.3 PTC Therapeutics
4.2.4 Skyhawk Therapeutics
4.3 Selected Technology Profile
4.3.1 RNA Splicing Platform
4.4 Drug Candidate Profiles
5 Direct RNA Targeting by Small Molecules
5.1.3 Targets and Indications
5.1.4 Partnering and Financing
5.1.5 Comparative Assessment
5.2.1 Arrakis Therapeutics
5.2.2 Expansion Therapeutics
5.2.3 Novation Pharmaceuticals
5.2.6 Saverna Therapeutics
5.2.7 Target RNA
6 Indirect RNA-Targeted (Epitranscriptomic) Small Molecules
6.1.3 Targets and Indications
6.1.4 Partnering and Financing
6.1.5 Comparative Assessment
6.2 Company Profiles
6.2.1 AC Immune
6.2.2 Accent Therapeutics
6.2.3 EPICS Therapeutics
6.2.4 Gotham Therapeutics
6.2.5 ImStar Therapeutics
6.2.6 STORM Therapeutics
6.2.7 Twentyeight-Seven Therapeutics
7 Major Pharmaceutical Companies as Stakeholders in RNA-Targeted Small Molecule R&D
7.2.2 Boehringer Ingelheim
7.2.3 Bristol-Myers Squibb
7.2.5 Eli Lilly
7.2.10 Takeda Pharmaceutical Co
8 Outlook and Perspectives
Addendum 1: Small Molecule mRNA Translation Regulators
Addendum 2: Small Molecule RNA Splicing Modifiers
Addendum 3: Direct RNA-Targeted Small Molecules
Addendum 4: Indirect RNA-Targeted Small Molecules (Epitranscriptomics)
Table 1 Overview of Small Molecule Translation Regulator Companies
Table 2 Key Features of Technologies to Discover Small Molecule mRNA Translation Regulators
Table 3 Targets of Small Molecule mRNA Translation Regulator R&D Programs
Table 4 Profiles for Selected Small Molecule mRNA Translation Regulators
Table 5 Financing of Small Molecule RNA Translation Regulator Companies by Investors and Collaboration Partners
Table 6 Comparative Assessment of Small Molecule mRNA Translation Regulator Companies
Table 7 Overview of Companies with Small Molecule RNA Splicing Modifiers
Table 8 Key Features of Technologies to Discover Small Molecule RNA Splicing Modifiers
Table 9 Targets/Indications of Small Molecule RNA Splicing Modifier R&D Programs
Table 10 Profiles for Selected Small Molecule mRNA Translation Regulators
Table 11 Financing of RNA Splicing Modifier Companies by Investors and Collaboration Partners
Table 12 Comparative Assessment of Small Molecule RNA Splicing Modifier Companies
Table 13 Skyhawk Therapeutics‘ Strategic Collaborations with Major Biopharmaceutical Companies for mRNA Splicing Modifiers Discovered by SkySTAR Technology
Table 14 Overview of Companies with Direct RNA-Targeted Small Molecules
Table 15 Key Features of Technologies to Discover Direct RNA-Targeted Small Molecules
Table 16 Targets/Indications of Direct RNA-Targeted Small Molecule R&D Programs
Table 17 Financing of Direct RNA-Targeted Small Molecule Companies by Investors and Collaboration Partners
Table 18 Comparative Assessment of Direct RNA-Targeted Small Molecule Companies
Table 19 Overview of Companies with Epitranscriptomic Small Molecule Modulators
Table 20 Key Features of Technologies to Discover Epitranscriptomic Small Molecule Modulators
Table 21 Targets/Indications of Epitranscriptomic Small Molecule Modulator R&D Programs
Table 22 Financing of Epitranscriptomic Small Molecule Modulators Companies by Investors and Collaboration Partners
Table 23 Comparative Assessment of Epitranscriptomic Small Molecule Modulator Companies
Table 24 Major Pharmaceutical Companies as Stakeholders in RNA-Targeted Small Molecule R&D
Table 25 Comparison of Four Approaches in RNA-Targeted Small Molecule R&D
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