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 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 the dotted lines represent zero to three double bonds, provided that no two double bonds are adjacent to one another;
o, p, and u are, independently, 0 or 1;
q and t are, independently, 0, 1, 2, 3, 4, 5, 6, or 7;
X 4 and X 5 are each, independently, CH 2 , O, S, SO, SO 2 , or NR 13 ;
each R 6 and R 7 are, independently, hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, 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 carbocyclyl, 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 6 and R 7 combine with the carbon atom to which they are bound to form C═O or R 6 and R 7 combine with the carbon atom to which they are bound to form an optionally substituted C 3 -C 10 carbocyclyl or optionally substituted C 2 -C 9 heterocyclyl;
each R 8 is, independently, hydroxyl, optionally substituted amino, halogen, thiol, 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 carbocyclyl, 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, or optionally substituted C 2 -C 9 heterocyclyl C 1 -C 6 alkyl or two R 8 combine with the carbon atoms to which they are bound to form an optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 6 -C 10 aryl, or optionally substituted C 2 -C 9 heteroaryl;
R 13 are each, independently, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, C 3 -C 7 carbocyclyl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, or optionally substituted C 3 -C 7 carbocyclyl C 1 -C 6 alkyl;
R 14 is hydrogen, hydroxyl, 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 carbocyclyl, 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;
X 7 is O, S, SO, SO 2 , or NR 19 ;
R 17 is hydrogen, hydroxyl, or optionally substituted C 1 -C 6 alkyl;
each R 18 is, independently, hydroxyl, optionally substituted amino, halogen, thiol, 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 carbocyclyl, 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, or optionally substituted C 2 -C 9 heterocyclyl C 1 -C 6 alkyl;
R 19 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, C 3 -C 7 carbocyclyl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, or optionally substituted C 3 -C 7 carbocyclyl C 1 -C 6 alkyl;
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 with the carbon atom to which they are bound to form C═O; and
R 33 is hydrogen or C═O, provided that no double bond is adjacent to a C═O.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 31 is hydrogen.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 32 is hydroxyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 5 is O.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 7 is O.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein t is 1.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 18 is methyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 14 is optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl or optionally substituted C 2 -C 9 heteroaryl C 1 -C 6 alkyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:
wherein v is 1 or 2;
Ar is optionally substituted aryl or optionally substituted heteroaryl; and
each R 33 and each R 34 is, 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, or optionally substituted C 2 -C 9 heterocyclyl C 1 -C 6 alkyl.
10. A presenter protein/compound complex comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a presenter protein.
11. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
12. A method of modulating a target protein comprising contacting said target protein with a modulating amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
13. 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.
14. A method of inhibiting prolyl isomerase activity comprising contacting a cell expressing said prolyl isomerase with a compound of claim 1 , or a pharmaceutically acceptable salt thereof, under conditions that permit the formation of a complex between said compound and said prolyl isomerase, thereby inhibiting the prolyl isomerase activity.
15. 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.
16. A tripartite complex including (i) a target protein and (ii) a presenter protein/compound complex of claim 10 .