Specificity, synergy, and mechanisms of splice-modifying drugs

Ishigami, Yuma, Wong, Mandy S, Martí-Gómez, Carlos, Ayaz, Andalus, Kooshkbaghi, Mahdi, Hanson, Sonya, McCandlish, David M, Krainer, Adrian R, Kinney, Justin B (December 2022) Specificity, synergy, and mechanisms of splice-modifying drugs. (Public Dataset) (Submitted)

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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 disprove 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 > 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 > antisense diseases & disorders > cancer > drugs and therapies
CSHL Authors:	Wong, Mandy Sze Ayaz, Andalus Kooshkbaghi, Mahdi McCandlish, David Krainer, Adrian R. Kinney, Justin B. Ishigami, Yuma Marti Gomez Aldaravi Carlos
Communities:	CSHL labs > Kinney lab CSHL labs > Krainer lab CSHL labs > McCandlish lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	31 December 2022
Date Deposited:	06 Nov 2023 13:27
Last Modified:	06 Nov 2023 13:27
Related URLs:	Publisher
Dataset ID:	GEO: GSE221868
URI:	https://repository.cshl.edu/id/eprint/41302

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