Identification of stabilizers of multimeric proteins

摘要

Disclosed herein are compounds and compositions thereof which find use in increasing stability of TTR tetramers reducing its tendency to misfold and form aggregates. Also provided herein are methods for using these compounds and compositions for increasing stability of TTR and thereby decreasing aggregate formation by TTR. Also disclosed herein are methods to screen for candidate compounds that increase stability of TTR. Also disclosed herein are heterobifunctional compounds that include a TTR binding compound connected to a targeting moiety via a linker, for use in disrupting PPIs of a target protein.

主权项

1. A method of decreasing TTR amyloid fibril formation, the method comprising contacting TTR with a pharmaceutical composition comprising a compound of formula (XVII): wherein L is a linker of about 1 to 8 atoms in length; R51 and R52 are selected from an alkyl, an aryl, an alkoxy, an aryloxy, a hydroxyl, a heterocyclic group, a halo, a nitro and a cyano; R53 is selected from hydrogen, an alkyl, an aryl and a heterocyclic group; and R54 is an aryl group, wherein the contacting decreases TTR amyloid fibril formation.