Project Catalyst
Project Catalyst
Ellen Welch, a research group leader at PTC Therapeutics in South Plainfield NJ introduced Project Catalyst,
which was started two years ago and which is supported by Parent Project in the USA. This is an example of how a dedicated small company uses the most modern automated techniques to find among about 200,000 small-molecular weight compounds the very few that could possibly be candidates for drugs that would do what was discussed in the previous three paragraphs: upregulation of utrophin, downregulation of myostatin, upregulation of the musclespecific isoform of IGF-1, and, in addition, upregulation of alpha-7-integrin.
Experience during the development of PTC124 for stop-codon read-through helped to optimize the automatic screening methods to modulate the activity of all four drug target molecules. The test procedure to measure the activities is based on a reporter protein system: the different re_gulatory sequences found at the ends of the target mRNAs (known as the untranslated regions [UTRs]) for each of the four targets were combined with the gene for the enzyme luciferase that normally produces light in fireflies. This firefly construct was introduced into kidney cells in such a way that in the presence of an active compound, the light intensity of the luciferase reporter would be either increased or decreased. The vast majority 12 of inactive compounds would not change significantly the light intensity. Measuring precisely and automatically light intensities in a very small volume of a sample preparation is much easier than analyzing the biological effect of the targets utrophin, myostatin, IGF-1, and alpha-7-integrin.
Two high-throughput screens were performed for each of the four targets. Among the 200,000 tested compounds several could be identified that either upregulated utrophin, IGF-1, or alpha-7-integrin, or that downregulated myostatin. All these "hits", compounds with at least some of the desired properties, are now being optimized by varying their structure. This will occupy many chemists for several years. E.g., for the optimization of the read-through drug PTC 124, about 4,000 chemical modifications were made to the originally identified active structure during two years of laboratory work. The next steps in the preclinical development of the new potential Duchenne drugs will also take several years.
In addition to the structural changes, there will be a detailed investigation of the biological properties of the most active molecules including studies in cell culture and in living mice of possible toxicity, of the metabolism, and of the pharmacokinetic behavior, i.e., of the biochemical changes inside a living organism which might produce, but hopefully not, undesirable side effects. The clinical testing in Duchenne patients of the most promising substances will then follow and will require a few more years.
From Günter Scheuerbrandt Report of the PPMD Conference 2006