COMPOUNDS THAT PARTICIPATE IN COOPERATIVE BINDING AND USES THEREOF
The invention features compounds (e.g., macrocyclic compounds) capable of modulating biological processes, for example through binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein). These compounds bind endogenous intracellular presenter proteins, such as the FKBPs or cyclophilins, and the resulting binary complexes selectively bind and modulate the activity of intracellular target proteins. Formation of a tripartite complex among the presenter protein, the compound, and the target protein is driven by both protein-compound and protein-protein interactions, and both are required for modulation of the targeted protein's activity. In some embodiments, the compounds of the invention “re-program” the binding of the presenter proteins to protein targets that either do not normally bind to the presenter protein (e.g., do not show detectable binding in mammalian cells absent the compound). In some embodiments, provided compounds “re-program” presenter protein binding to greatly enhance interaction with a particular target with which it may have some interaction absent the compound. Interactions achieved through such reprogramming result in an ability to modulate the activity of these new targets.
1 - 66 . (canceled)
67 . A tripartite complex comprising (i) a KRAS protein and (ii) a presenter protein/compound complex, wherein
the presenter protein is a member of the cyclophilin family;
the compound is a macrocycle comprising: 14 to 40 ring atoms, a KRAS target protein interacting moiety, and a cyclophilin binding moiety; and
the presenter protein/compound complex binds to the KRAS protein with at least 5-fold greater affinity than the affinity of each of the compound and the presenter protein to the KRAS protein in the absence of forming the presenter protein/compound complex.
68 . The tripartite complex of claim 67 , wherein the compound comprises the structure:
wherein A is a KRAS target protein interacting moiety;
B is a cyclophilin binding moiety; and
L 1 and L 2 are each a linker independently selected from a bond and a linear chain of up to 10 atoms.
69 . The tripartite complex of claim 67 , wherein the cyclophilin protein is cyclophilin A.
70 . The tripartite complex of claim 67 , wherein the binding of the presenter protein/compound complex to the KRAS protein is non-covalent.
71 . The tripartite complex of claim 67 wherein the binding of the presenter protein/compound complex to the KRAS protein is covalent.
72 . A presenter protein/compound complex wherein
the presenter protein is a member of the cyclophilin family; and
the compound is a macrocycle comprising 14 to 40 ring atoms.
73 . The complex of claim 72 , wherein the compound comprises the structure:
wherein A is a KRAS target protein interacting moiety;
B is a cyclophilin binding moiety; and
L 1 and L 2 are each a linker independently selected from a bond and a linear chain of up to 10 atoms.
74 . The complex of claim 72 , wherein the cyclophilin protein is cyclophilin A.
75 . A method of modulating a KRAS protein, the method comprising contacting the KRAS protein with a modulating amount of the presenter protein/compound complex of claim 72 .
76 . The method of claim 75 , wherein the binding of the presenter protein/compound complex to the KRAS protein is non-covalent.
77 . The method of claim 75 , wherein the binding of the presenter protein/compound complex to the KRAS protein is covalent.
78 . A macrocyclic compound, or a pharmaceutically acceptable salt thereof, comprising 14 to 40 ring atoms, a KRAS target protein interacting moiety, and a cyclophilin binding moiety.
79 . The compound of claim 78 having the structure:
or a pharmaceutically acceptable salt thereof, wherein
A is a KRAS target protein interacting moiety;
B is a cyclophilin binding moiety; and
L 1 and L 2 are each a linker independently selected from a bond and a linear chain of up to 10 atoms.
80 . The compound of claim 78 , wherein the cyclophilin protein is cyclophilin A.
81 . A method of modulating a KRAS protein, the method comprising contacting the KRAS protein with a modulating amount of a compound of claim 78 .
82 . The method of claim 78 , wherein the binding of the compound to the KRAS protein is non-covalent.
83 . The method of claim 78 , wherein the binding of the compound to the KRAS protein is covalent.