Specificity, synergy, and mechanisms of splice-modifying drugs

Ishigami, Yuma, Wong, Mandy S, Martí-Gómez, Carlos, Ayaz, Andalus, Kooshkbaghi, Mahdi, Hanson, Sonya M, McCandlish, David M, Krainer, Adrian R, Kinney, Justin B (February 2024) Specificity, synergy, and mechanisms of splice-modifying drugs. Nature Communications, 15 (1). p. 1880. ISSN 2041-1723 (Public Dataset)

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Abstract

Drugs that target pre-mRNA splicing hold great therapeutic potential, but the quantitative understanding of how these drugs work is limited. Here we introduce mechanistically interpretable quantitative models for the sequence-specific and concentration-dependent behavior of splice-modifying drugs. Using massively parallel splicing assays, RNA-seq experiments, and precision dose-response curves, we obtain quantitative models for two small-molecule drugs, risdiplam and branaplam, developed for treating spinal muscular atrophy. The results quantitatively characterize the specificities of risdiplam and branaplam for 5' splice site sequences, suggest that branaplam recognizes 5' splice sites via two distinct interaction modes, and contradict the prevailing two-site hypothesis for risdiplam activity at SMN2 exon 7. The results also show that anomalous single-drug cooperativity, as well as multi-drug synergy, are widespread among small-molecule drugs and antisense-oligonucleotide drugs that promote exon inclusion. Our quantitative models thus clarify the mechanisms of existing treatments and provide a basis for the rational development of new therapies.

Item Type: Paper
Subjects: bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > oligonucleotide
CSHL Authors:
Communities: CSHL labs > Kinney lab
CSHL labs > Krainer lab
CSHL labs > McCandlish lab
CSHL Cancer Center Program
CSHL Cancer Center Program > Gene Regulation and Inheritance Program
CSHL Cancer Center Shared Resources
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 29 February 2024
Date Deposited: 07 Mar 2024 13:45
Last Modified: 07 Mar 2024 13:45
PMCID: PMC10904865
Related URLs:
Dataset ID:
  • GEO: GSE221868
  • https://github.com/jbkinney/22_drugs
  • https://doi.org/10.5281/zenodo.8353692
URI: https://repository.cshl.edu/id/eprint/41453

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