Approach to Drug Discovery

FoldRx has taken several approaches to identifying small molecules that mitigate the consequences of protein misfolding. As exemplified by the transthyretin (TTR) program, we have used existing detailed knowledge of TTR’s misfolding pathway to find and optimize small molecules that bind to TTR, thereby stabilizing the native state to inhibit aggregation and amyloid deposition. However, for many proteins, the misfolding pathway is not known. In this case, as exemplified in our Parkinson’s disease program by α-synuclein, we employed a different strategy. We developed cellular assays of proteotoxicity and identified compounds that restore viability. Finally, in the case of mutant cargo proteins such as ΔF508 CFTR, we established assays for modulators of ER to Golgi traffic. With the exception of TTR, we have targeted well conserved cellular processes. Our pathway assay platform begins with the model organism yeast and active small molecules are rapidly advanced to disease-relevant assays.