BIO-6553

BIO-6553 : Splicing modulator of HTT

Structure

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Probe BIO-6553 is in the process of SERP review.

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Information

Splicing modulator

up to 1 uM

In Vitro Validations

No in Vitro Validations

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay, off target (cells): RNA-seq analysis in SH-SY5Y cells to identify both differentially expressed genes (DEGs) and differentially spliced genes (DSGs) across the whole transcriptome.

Probe Selectivity in Cell:

At three times its IC50, BIO-6553 (23) significantly regulated 11 additional genes and induced 23 splicing events. Motif enrichment analysis revealed a significant enrichment of adenine at the −3 position in BIO-6553-induced splicing events.

Potency assay (off target): Kinase off-targets of 23 were evaluated at 1 μM in a broad kinome panel (Eurofins: 468 kinases).

Probe Selectivity in Vitro:

Despite having multiple potential hinge binding motifs, no kinase showed greater than 80% inhibition, demonstrating that lead candidate has good off-target selectivity.

Potency assay, off target (cells): RASL-seq assay (RNA-mediated oligonucleotide annealing, selection, and ligation sequencing) in SH-SY5Y (human neuroblastoma) cells that generated IC50′s and therefore selectivity windows over HTT for 126 unique off-targets.

Probe Selectivity in Cell:

The RASL-seq panel was composed of off-target genes previously identified by genome-wide RNA-seq analysis of internal leads and known splice modulators such as risdiplam and branaplam. Despite not having the highest RASL-seq selectivity ratio, BIO-6553 (23) was ultimately prioritized due to its overall optimal profile across other key parameters.

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