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Conclusion References: (1) Alhamadsheh MM, et al. Potent kinetic stabilizers that prevent transthyretinmediated cardiomyocyte proteotoxicity. Sci Transl Med. 2011;3(97):97ra81. (2) . Penchala S, et al. AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy associated V122I transthyretin. Proc Natl Acad Sci U S A. 2013,110(24):9992-7 Figure 2. Crystal structures highlighting the similar interactions caused by the trans-suppressor stabilizing T119M mutation and binding of AG10 to TTR. Quaternary structure of (a) AG10 bound to V122I-TTR (PDB: 4HIQ). (b) WT-TTR (PDB: 3CFM). (c) tafamidis bound to V122I-TTR (PDB: 4HIS). (d) T119M-TTR variant (PDB: 1FHN) with dashed lines and red circles highlighting key interactions between the hydroxyl groups of S117/S117’. Figure 1. (a) Binding affinity of stabilizers to TTR in buffer. (b) %TTR stabilization in serum by stabilizers using Western blot; AG10 (10 μM), tafamidis (20 μM), tolcapone (20 μM), diflunisal (200 μM). (c,d) %TTR occupancy in human serum by fluorescence probe exclusion (FPE) assay.

european heart journal

P5846AG10, an orally available, novel transthyretin (TTR) stabilizer: integrated preclinical evaluation predicts a highly effective treatment for TTR amyloid cardiomyopathy