Although FDA has yet to approve any drugs for the treatment of transthyretin-based cardiac amyloidosis, a disease caused by aggregation of proteins in the heart, a study adds more candidates to the list of possibilities (Sci. Transl. Med., DOI: 10.1126/scitranslmed.3002473). Transthyretin is a tetrameric protein that transports the hormone thyroxine throughout the body. When the protein becomes unstable, particularly because of a mutation, it aggregates and can cause heart arrhythmia and failure. Current transthyretin-stabilizing drugs in clinical trials, such as tafamidis, were designed “rationally” on the basis of thyroxine’s structure. Some of these candidates, however, inhibit cyclooxygenase enzymes, which might pose additional cardiovascular risk. Isabella A. Graef of Stanford University School of Medicine, Jeffery W. Kelly and Ian A. Wilson of Scripps Research Institute, and coworkers developed a fluorescence polarization assay and screened 130,000 small molecules for binding transthyretin. They then used a battery of other tests to narrow the field of 200 hits to a handful of promising candidates. Their top picks—compounds with no previously known biological targets—do not inhibit cyclooxygenase or bind to the thyroid hormone receptor.