Dynamic inhibitors of heat shock protein 90

1. An inhibitor of heat shock protein 90 (HSP90), the inhibitor being a coumermycin A1 analog that has a structure of Scaffold 1,

wherein:

R 1 and R 2 each independently includes S2 or S3

X 1 , X 2 , Y 1 , and Y 2 each independently includes a moiety independently selected from hydrogen, halogens, hydroxyls, alkoxys, straight aliphatics, branched aliphatics, cyclic aliphatics, heterocyclic aliphatics, substituted aliphatics, unsubstituted aliphatics, saturated aliphatics, unsaturated aliphatics, aromatics, polyaromatics, substituted aromatics, hetero-aromatics, amines, primary amines, secondary amines, tertiary amines, aliphatic amines, carbonyls, carboxyls, amides, esters, amino acids, peptides, polypeptides, sugars, sugar mimics, or combinations thereof, the aliphatic groups having carbon chains of carbons or hetero atoms or O, N, S, or P; and

linker including a straight aliphatic, branched aliphatic, cyclic aliphatic, heterocyclic aliphatic, substituted aliphatic, unsubstituted aliphatic, saturated aliphatic, unsaturated aliphatic, aromatic, polyaromatic, substituted aromatic, hetero-aromatic, amine, primary amine, secondary amine, tertiary amine, aliphatic amine, carbonyl, carboxyl, amide, ester, amino acid, peptide, polypeptide, sugars, sugar mimic, or combinations thereof.

2. The inhibitor of claim 1 , wherein X 1 or X 2 are independently hydrogen or methoxy.

3. The inhibitor of claim 1 , wherein Y 1 or Y 2 are independently methyl or methoxy.

4. The inhibitor of claim 1 , wherein linker includes a saturated or unsaturated aliphatic having C 3 -C 10 , a 1-1′-biphenyl with a methoxy substituent on each phenyl ring, a 6H-benzo[c]chromene compound, 6,7-dihydrodibenzo[b,d]oxepine, or 7,8-dihydro-6H-dibenzo[b,d]oxocine.

5. The inhibitor of claim 1 , wherein:

X 1 or X 2 are independently hydrogen or methoxy;

Y 1 or Y 2 are independently methyl or methoxy; and

linker includes a saturated or unsaturated aliphatic having C 3 -C 10 , a 1-1′-biphenyl with a methoxy substituent on each phenyl ring, a 6H-benzo[c]chromene compound, 6,7-dihydrodibenzo[b,d]oxepine, or 7,8-dihydro-6H-dibenzo[b,d]oxocine.

6. The inhibitor of claim 1 , wherein linker is L1, L2, or L3, with n for L1 being 0, 1, 2, or 3, and n for L3 being 1, 2, or 3,

7. The inhibitor of claim 1 , wherein the linker is devoid of aryl, heteroaryl or olefin.

8. The inhibitor of claim 1 , wherein the coumermycin A1 analog has a structure of Scaffold 2, wherein n and m are independently integers

9. The inhibitor of claim 1 , wherein the coumermycin A1 analog has a structure of Scaffold 3, wherein n is an integer

10. The inhibitor of claim 1 , wherein the coumermycin A1 analog is conformationally constrained and has a structure of Scaffold 4,

n1=0, 2,6-dicarboxamide, pseudo-trans;

n1=1, 4,8-dicarboxamide, pseudo-trans;

n1=1, 3,8-dicarboxamide, trans;

n1=1, 2,8-dicarboxamide, pseudo-cis; or

n1=2, 2,6-dicarboxamide, pseudo-trans

11. The inhibitor of claim 1 , wherein the coumermycin A1 analog has a structure of Scaffold 6, R is R 1 , X is X 1 , Y is Y 1 , and n is 1-4,

12. The inhibitor of claim 1 , wherein the coumermycin A1 analog has a structure of Scaffold 7, n is 1-5,

13. The inhibitor of claim 1 , wherein the coumermycin A1 analog has a structure of Scaffold 9, R 3 is R 1 ,

14. A coumermycin A1 analog that has a structure of Scaffold 10, n2 is 1-4,

15. A method of inhibiting heat shock protein 90 (HSP90), the method comprising:

providing a coumermycin A1 analog in accordance with claim 1 ; and

contacting the coumermycin A1 analog with a HSP90 so as to inhibit the HSP90.

16. The method of claim 15 , wherein the HSP90 is in a cancerous cell.

17. The method of claim 15 , wherein the HSP90 is in a patient that has cancer.

18. The method of claim 15 , wherein the coumermycin A1 analog has HSP90 inhibiting activity of greater than 10 times the activity of coumermycin A1.

19. The method of claim 15 , wherein the coumermycin A1 analog has an anti-proliferative activity of greater than IC 50 =70 μM.

20. A method of degrading a HSP90-dependent client protein, the method comprising:

providing a coumermycin A1 analog in accordance with claim 2 ; and

contacting the coumermycin A1 analog with a HSP90 or HSP90-dependent client protein so as to degrade the client protein.

21. The method of claim 20 , wherein the client protein is Her-2, Raf, or Akt.

22. A method of inhibiting cell proliferation, the method comprising:

providing a coumermycin A1 analog in accordance with claim 2 ; and

contacting the coumermycin A1 analog with a potentially proliferative cell in a sufficient amount to inhibit proliferation of the cell.

23. The inhibitor of claim 11 , wherein:

X is selected from the group consisting of hydrogen, methyl, methoxy,

Y is selected from the group consisting of methyl and methoxy,

n is selected from 1, 2, 3, or 4.

24. The inhibitor of claim 23 , wherein the coumermycin A1 analog includes one of compounds 26-36 or 38 having R, n, X, and Y defined as follows:

Compound #

R

n

X

Y

26

1

H

Me

29

2

H

Me

32

3

H

Me

35

4

H

Me

27

1

OMe

Me

30

2

OMe

Me

33

3

OMe

Me

28

1

H

OMe

31

2

H

OMe

34

3

H

OMe

36

1

H

Me

38

2

H

 Me.

25. The inhibitor of claim 12 , wherein n is 1, 3, or 5.

26. An inhibitor of heat shock protein 90 (HSP90), the inhibitor being a coumermycin A1 analog that has a structure of Scaffold 1,

wherein:

R 1 , R 2 , X 1 , X 2 , Y 1 , and Y 2 each independently includes a moiety independently selected from hydrogen, halogens, hydroxyls, alkoxys, straight aliphatics, branched aliphatics, cyclic aliphatics, heterocyclic aliphatics, substituted aliphatics, unsubstituted aliphatics, saturated aliphatics, unsaturated aliphatics, aromatics, polyaromatics, substituted aromatics, heteroaromatics, amines, primary amines, secondary amines, tertiary amines, aliphatic amines, carbonyls, carboxyls, amides, esters, amino acids, peptides, polypeptides, sugars, sugar mimics, or combinations thereof, the aliphatic groups having carbon chains of carbons or hetero atoms or O, N, S, or P; provided that R 1 and R 2 are not a noviose sugar moiety; and

linker is L1, L2, or L3, with n for L1 being 0, 1, 2, or 3, and n for L3 being 1, 2, or 3,

27. The inhibitor of claim 26 , wherein R 1 and R 2 are independently S2 or S3,