molecules of the month

compound 1 is a CD33 pre-mRNA splicing modulator that increases CD33 exon 2 skipping in cells. CD33/Siglec 3 regulates microglia activity, and genetic alterations of CD33 are associated with protection from Alzheimer’s. Alternative splicing of CD33 with exclusion of exon 2 is hypothesized to copy the protective effect of the human genetic variants. The hit is an interesting proof-of-concept for pre-mRNA splicing manipulation by a small molecule. It was identified from an HTS of the full Pfizer library of 3.1M compounds, using a reporter-gene-based phenotypic CD33 splicing assay. The hit was derived from a previous PCSK9 translational stalling project. A high-content imaging assay for cytotoxicity was used to qualify hits. Unfortunately, despite promising initial SAR, the program was discontinued and…