Résumé :
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PTC Therapeutics, Inc. (PTC) has established a new program to identify compounds that modulate the levels of the survival of motor neuron (SMN) protein at the post-transcriptional level. The program is driven by three innovative approaches. The first approach utilizes PTC’s proprietary drug discovery platform technology called GEMS (Gene Expression Modulation by Small-molecules) to identify small molecules that up- or down-regulate the production of proteins, such as SMN, via the untranslated regions of mRNAs. The second approach utilizes PTC’s nonsense suppression platform to identify compounds that read through the aberrant stop codon present in the SMN?Ex7 mRNA, resulting in the increased stability of SMN?Ex7 protein that is present in all SMA patients. In the third approach, we are screening for small molecules that alter the splicing pattern of the SMN2 pre-mRNA thereby increasing the inclusion of exon 7 into SMN2 transcripts. We conducted high-throughput screens (HTS) based on these three approaches and have identified lead compounds that increase the levels of functional SMN. The molecules identified have been characterized for biological, pharmaceutical and pharmacological properties. The next stage of this drug discovery effort will include medicinal chemical optimization of the most promising lead molecules with the ultimate goal of identifying a drug candidate for preclinical and clinical development.
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