IP Library › Granted Patent US 9,035,024

Granted Patent B2

US 9,035,024 · App. 13/861,959 · Granted May 19, 2015

Compounds that inhibit Hsp90 protein-protein interactions with IAP proteins

Inventors: Dario C. Altieri (Worcester, MA); Janet Plescia (Meriden, CT); Whitney Salz (Acton, MA)

Assignee: University of Massachusetts

C07K14/4747 A61K38/00 G01N33/574 G01N2510/00 A61K39/39558

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Quick Facts

Patent No.: US 9,035,024
App. No.: 13/861,959
Granted: May 19, 2015
Kind: B2

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Abstract

Disclosed herein are compounds that inhibit Hsp90 interactions with IAP proteins, such as Survivin, XIAP, cIAP1, or cIAP2, and methods for identifying and using such compounds.

Claims (32)

1. A method of treating breast cancer, the method comprising:

selecting a subject diagnosed as having breast cancer associated with overexpression of Survivin; and

administering to the selected subject a therapeutically effective amount of a pharmaceutical composition comprising a compound:

(i) consisting of a D-amino acid peptide selected from the group consisting of: (D-Leu)-(D-Phe)-(D-Ala)-(D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys); (D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His); and (D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys); or

(ii) comprising the formula X-A or A-X, wherein A consists of a D-amino acid sequence selected from the group consisting of: (D-Leu)-(D-Phe)-(D-Ala)-(D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys); (D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His); and (D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys); and X consists of an internalization peptide sequence of a protein selected from the group consisting of: Tat, Antennapedia, VP22, Pep-1, and transportan, or a retro-inverso version of said internalization peptide sequence.

2. The method of claim 1 , wherein the compound comprises the formula X-A or A-X, wherein:

A consists of a D-amino acid sequence selected from the group consisting of: (D-Leu)-(D-Phe)-(D-Ala)-(D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys); (D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His); and (D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys); and

X consists of an internalization peptide sequence of a protein selected from the group consisting of: Tat, Antennapedia, VP22, Pep-1, and transportan, or a retro-inverso version of said internalization peptide sequence.

3. The method of claim 2 , wherein the compound comprises a D-amino acid sequence selected from:

(D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His);

(D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Leu)-(D-Phe)-(D-Ala)-(D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys); and

(D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys).

4. The method of claim 3 , wherein the compound comprises the D-amino acid sequence (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Leu)-(D-Phe)-(D-Ala)-(D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys).

5. The method of claim 4 , wherein the compound consists of the D-amino acid peptide (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Leu)-(D-Phe)-(D-Ala)-(D Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys).

6. The method of claim 3 , wherein the compound comprises the D-amino acid sequence (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His) or the D-amino acid sequence (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys).

7. The method of claim 6 , wherein the compound consists of the D-amino acid peptide (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His) or the D-amino acid peptide (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys).

8. The method of claim 1 , wherein the pharmaceutical composition is administered by intravenous or subcutaneous administration.

9. A method of inducing apoptosis in a breast tumor cell in a subject, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an isolated compound:

10. The method of claim 9 , wherein the compound comprises the formula X-A or A-X, wherein:

11. The method of claim 10 , wherein the compound comprises a D-amino acid sequence selected from:

(D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His);

(D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys).

12. The method of claim 11 , wherein the compound comprises the D-amino acid sequence (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Leu)-(D-Phe)-(D-Ala)-(D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys).

13. The method of claim 12 , wherein the compound consists of the D-amino acid peptide (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Leu)-(D-Phe)-(D-Ala)-(D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys).

14. The method of claim 11 , wherein the compound comprises the D-amino acid sequence (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His) or the D-amino acid sequence (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys).

15. The method of claim 14 , wherein the compound consists of the D-amino acid peptide (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Cys)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His) or the D-amino acid peptide (D-Lys)-(D-Lys)-(D-Trp)-(D-Lys)-(D-Met)-(D-Arg)-(D-Arg)-(D-Asn)-(D-Gln)-(D-Phe)-(D-Trp)-(D-Val)-(D-Lys)-(D-Val)-(D-Gln)-(D-Arg)-(D-Gly)-(D-Ser)-(D-Ser)-(D-His)-(D-Lys).

16. The method of claim 9 , wherein the pharmaceutical composition is administered by intravenous or subcutaneous administration.

Assignments (2)

CONFIRMATORY LICENSE Recorded Apr 17, 2017

From: UNIVERSITY OF MASSACHUSETTS MEDICAL SCH

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 042265/0812 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 10, 2014

From: ALTIERI, DARIO C.; PLESCIA, JANET; SALZ, WHITNEY

To: UNIVERSITY OF MASSACHUSETTS

Reel/Frame 031934/0929 →

Continuity (4)

Continuation 12033210 · Feb 19, 2008

Division 11187230 · Jul 22, 2005

Provisional Application 60590584 · Jul 23, 2004

Related Publication 20140086924A1 · Mar 27, 2014