Compounds that participate in cooperative binding and uses thereof
The invention features compounds (e.g., macrocyclic compounds) capable of modulating biological processes, for ex ample 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 such as CEP250. 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 the target protein. 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 target protein activity.
1. A macrocyclic compound, or a pharmaceutically acceptable salt thereof, having the structure:
wherein A is a target protein interacting moiety described by the structure of Formula XIII:
wherein the dotted lines represent zero to three double bonds, provided that no two double bonds are adjacent to one another;
R 31 and R 32 are independently hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted amino acid, optionally substituted C 1 -C 6 acyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 4 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 2 -C 9 heterocyclyl C 1 -C 6 alkyl, or R 31 and R 32 combine to form C═O;
R 33 is hydrogen or C═O, provided that no double bond is adjacent to a C═O; and
B is a presenter protein binding moiety described by a structure selected from:
and each of L 1 and L 2 is, independently, a linker.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the target protein interacting moiety is described by a structure selected from:
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the target protein interacting moiety is described by a structure selected from:
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the presenter protein binding moiety is described by a structure selected from:
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 and L 2 are each, independently, selected from a bond or a linear chain of up to 10 atoms, independently selected from carbon, nitrogen, oxygen, sulfur and phosphorous atoms, wherein each atom in the chain is optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxyl, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylsulfonate, arylsulfonate, phosphoryl, and sulfonyl, and wherein any two atoms in the chain may be taken together with the substituents bound thereto to form a ring, wherein the ring may be further substituted and/or fused to one or more optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl rings.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein L 1 and L 2 are each a bond.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
the target protein interacting moiety is described by:
the presenter protein binding moiety is described by:
and L 1 and L 2 are each a bond.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
the target protein interacting moiety is described by:
the presenter protein binding moiety is described by:
and L 1 and L 2 are each a bond.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
the target protein interacting moiety is described by:
the presenter protein binding moiety is described by:
and L 1 and L 2 are each a bond.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
the target protein interacting moiety is described by:
wherein R 31 is hydrogen, and R 32 is hydroxyl;
the presenter protein binding moiety is described by:
and L 1 and L 2 are each a bond.
11. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
12. A presenter protein/compound complex comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a presenter protein.
13. A tripartite complex including (i) the presenter protein/compound complex of claim 12 ; and (ii) a target protein.
14. The tripartite complex of claim 13 , wherein the presenter protein is a prolyl isomerase.
15. The tripartite complex of claim 14 , wherein the target protein is CEP250.
16. A method of modulating a target protein comprising contacting a cell expressing said target protein and a presenter protein with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, under conditions wherein the compound can form a complex with the presenter protein and the resulting complex can bind to said target protein, thereby modulating said target protein.
17. The method of claim 16 , wherein the presenter protein is a prolyl isomerase.
18. The method of claim 17 , wherein the target protein is CEP250.
19. A method for the preparation of a compound of claim 1 comprising culturing a bacterial strain of the genus Streptomyces and isolating the compound from the fermentation broth.
20. A method of treating an infection comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.