DNA-encoded library versus RNA-encoded library selection enables design of an oncogenic noncoding RNA inhibitor

Abstract

Significance Drug discovery generally investigates one target at a time, in sharp contrast to living organisms, which mold ligands and targets by evolution of highly complex molecular interaction networks. We recapitulate this modality of discovery by encoding drug structures in DNA, allowing the entire DNA-encoded library to interact with thousands of RNA fold targets, and then decoding both drug and target by sequencing. This information serves as a filter to identify human RNAs aberrantly produced in cancer that are also binding partners of the discovered ligand, leading to a precision medicine candidate that selectively ablates an oncogenic noncoding RNA, reversing a disease-associated phenotype in cells.

Targeting RNA structures with small molecules

“…In particular, RNA-binding compounds on average have lower octanol–water partition coefficients (LogPs) than protein-binding compounds (ranges from two separate analyses: 0.16 ± 5 versus 2.0 ± 3.5 (ref. 109 ) and 1.02 versus 1.78 (ref. 283 ), respectively), greater topological polar surface areas (156 ± 118 versus 92 ± 144 Å 2 ) 109 , more hydrogen bond donors (5.2 ± 5 versus 2.0 ± 4) and acceptors (8.6 ± 6 versus 5.0 ± 6) 109 , and more heteroatom-containing aromatic rings (2.16 versus 1.25) 283 .…”

“… 109 ) and 1.02 versus 1.78 (ref. 283 ), respectively), greater topological polar surface areas (156 ± 118 versus 92 ± 144 Å 2 ) 109 , more hydrogen bond donors (5.2 ± 5 versus 2.0 ± 4) and acceptors (8.6 ± 6 versus 5.0 ± 6) 109 , and more heteroatom-containing aromatic rings (2.16 versus 1.25) 283 . An analysis by the Hargrove laboratory suggested that the shape of RNA binders is generally rod-like 283 .…”

“…Various studies have identified privileged scaffolds and chemotypes that confer affinity for RNA, for example, indole, 2-phenylindole, 2-phenyl benzimidazole, 2-phenylimidazole, methylpyrimidine-2,4-diamine and others 67 , 78 , 281 , 282 . Further, comparison of the physicochemical properties of RNA-binding molecules with those of FDA-approved drugs available in DrugBank revealed distinct differences 109 , 283 , 284 . In particular, RNA-binding compounds on average have lower octanol–water partition coefficients (LogPs) than protein-binding compounds (ranges from two separate analyses: 0.16 ± 5 versus 2.0 ± 3.5 (ref.…”

“…Because of the potential of nonspecific binding of the encoding DNA tag, nucleic acids and their binding proteins have been avoided. Thus far, the DEL technology has been applied only twice to nucleic acid targets: RNA 109 and highly structured DNA G-quartets 110 .…”

Development of on-DNA vinyl sulfone synthesis for DNA-encoded chemical libraries

“…1 By combining the merits of synthetic chemistry and DNA genetic barcoding, this technology generates a collection of numerous DNA-tagged compounds (from hundreds of millions to billions) via “split-and-pool” cycles, 2 which then are screened against therapeutic targets of interest (TOI). 3 The conjugated DNA tags that could be read out by the sequencing technique enable the identification of those high-affinity binders within a complex pool, thus rendering high throughput screening (HTS) at a lower cost and efficient time (Scheme 1a). 4 This competitive strategy featuring unique DNA barcodes, thereby, has been harnessed by both the pharmaceutical industry 5 and academia, 6 to facilitate the early stage of drug discovery, undoubtfully generating fruitful outcomes of clinical candidates represented by the RIPK1 inhibitor GSK2982772, 7 sEH inhibitor GSK2256294, 8 and autotaxin inhibitor X-165, 9 which were optimized from the corresponding DEL hits.…”