title: AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin.
abstract: The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.
authors.affiliation: Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, CA 95211, USA.
authors.forename: Sravan C
authors.initials: SC
authors.lastname: Penchala
authors.forename: Stephen
authors.initials: S
authors.lastname: Connelly
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Miki S
authors.initials: MS
authors.lastname: Park
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Baranczak
authors.forename: Irit
authors.initials: I
authors.lastname: Rappley
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Michaela
authors.initials: M
authors.lastname: Liedtke
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Witteles
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.forename: Natàlia
authors.initials: N
authors.lastname: Reixach
authors.forename: William K
authors.initials: WK
authors.lastname: Chan
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.forename: Isabella A
authors.initials: IA
authors.lastname: Graef
authors.forename: Mamoun M
authors.initials: MM
authors.lastname: Alhamadsheh
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D019540:Area Under Curve; D001565:Benzoates / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001583:Benzoxazoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011228:Prealbumin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D019817:Benzoic Acid
chemical_list: D000682:Amyloid; D001565:Benzoates; D001583:Benzoxazoles; D011228:Prealbumin; D011720:Pyrazoles; C547076:tafamidis; C000731204:acoramidis; D019817:Benzoic Acid
keywords: crystal structure; drug design