Small molecules that alter SRSF10-Mediated Alternative Splicing
Novel small molecules with demonstrated activity that (i) inhibit replication of drug-resistant strains of HIV; (ii) promote exon 7 inclusion in SMN2 in a patient-derived cell line and; (iii) reduce the transcription of BCLAF1 transcript variant in colon cancer cell lines
- Compounds employ a novel MOA to combat HIV replication that is effective against drug resistant strains.
- The small molecule series represents novel compositions of matter for broad IP coverage
- The therapeutic target, SRSF10-mediated splicing, has been linked to other disease indications that are under investigation including colon cancer and spinal muscular atrophy.
Despite the widespread success of current antiretroviral agents in reducing viral loads and HIV transmission, the development of viral resistance against these agents continues to complicate the therapeutic management of HIV. Currently, it is estimated that between 5-20% of treatment-naïve patients are resistant to at least one antiretroviral agent. The emergence of drug resistance in HIV requires the selection of alternate regimens and consequently leads to a marked increase in costs associated with patient care and monitoring.
HIV relies on host cell’s alternative splicing machinery for virus reproduction. By exploiting this required mechanism, researchers at UBC have developed a small molecule series that targets the host’s alternative splicing machinery, resulting in reduced viral replication through impaired transcription of Tat. Unlike current HAART therapeutics, this novel approach of targeting a host factor as opposed to a viral protein represents a previously unexploited mechanism of action that bypasses the development of new drug resistant strains.
The novel small molecules have demonstrated inhibitory activity against SRSF10 and hTRa2b-mediated splicing events. Recently, these splicing factors have been shown to be involved in oncogene alternative splicing in colon cancer and spinal muscular atrophy.