Tafamidis is a kinetic stabilizer of transthyretin (TTR) that prevents amyloidogenesis by wild-type and mutant TTRs.1 It binds to TTR with negative cooperativity (Kd1 = 3 nM; Kd2 = 278 nM) to stabilize the TTR dimer-dimer interface and inhibit tetrameric dissociation. Tafamidis stabilizes wild-type and clinically significant V30M and V122I mutant TTR amyloidogenic homotetramers (EC50s = 2.7-3.2 μM) under fibril-promoting, denaturing, and physiological conditions in vitro. It stabilizes TTR heterotetramers containing wild-type and mutant subunits ex vivo in human plasma derived from patients carrying V30M or V1221 mutations when used at a concentration of 7.2 μM. Formulations containing tafamidis have been used for the treatment of familial amyloid polyneuropathy.2
1.Bulawa, C.E., Connelly, S., Devit, M., et al.Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascadeProc. Natl. Acad. Sci. USA109(24)9629-9634(2012) 2.Scott, L.J.Tafamidis: A review of its use in familial amyloid polyneuropathyDrugs74(12)1371-1378(2014)