MODULAR PLATFORM FOR TARGETED THERAPEUTIC DELIVERY

• US 20090176705A1
• Filed: 10/22/2008
• Published: 07/09/2009
• Est. Priority Date: 10/22/2007
• Status: Active Grant

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: Hawkins, William G., McDunn, Jonathan E., Hotchkiss, Richard A., Mach, Robert H.
• Granted Patent: US 8,143,222 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 221/22 Bridged ring systems

Abstract

Pharmaceutical compounds, pharmaceutical compositions and methods of treatment are disclosed, wherein a compound comprises a targeting moiety which, in free form, binds a cell receptor with a dissociation constant K_d of less than about 10⁻⁷ M, and a pharmaceutically active moiety, wherein the targeting moiety is other than an oligopeptide, a polypeptide, a peptidomimetic, a protein or a protein domain, and wherein the targeting moiety and the pharmaceutically active moiety are covalently attached. In some aspects, the targeting moiety binds a sigma-2 receptor with high affinity and high specificity, and the pharmaceutically active moiety is a pro-apoptotic peptide moiety. Methods of cancer treatment are disclosed comprising administering a disclosed pharmaceutical compound to a subject in need of thereof. The treatments selectively induce apoptosis in cancer cells. These methods can further comprise co-administration of radiation therapy and/or an additional chemotherapeutic agent.

Claims

1. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof, comprising:

a) a targeting moiety which, in free form, binds a cell receptor with a dissociation constant K_d of less than about 10<sup>−

7</sup> M; and

b) a pharmaceutically active moiety

wherein the targeting moiety is other than an oligopeptide, a polypeptide, a peptidomimetic, a protein or a protein domain, and wherein the targeting moiety and the pharmaceutically active moiety are covalently attached.

2. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 1, wherein the targeting moiety has a molecular mass of less than about 400 Da.

3. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 1, wherein the cell receptor is a sigma-2 receptor, and wherein the targeting moiety is a N-substituted 9-azabicyclo[3.3.1]nonan-3α

-yl phenylcarbamate.

4. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 1, wherein the cell receptor is a sigma-2 receptor, and the targeting moiety comprises a dimethoxytetrahydroisoquinoline.

5. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 1, wherein the cell receptor is a dopamine D₂ receptor, and wherein the targeting moiety comprises an S-(−

) isomer of 3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide (IBZM).

6. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 1, wherein the cell receptor is a dopamine D₃ receptor, and wherein the targeting moiety comprises 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT).

7. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 1, wherein the targeting moiety is selected from the group consisting of colchicine, taxol, cytochalasin, latrunculin, chlorpromazine, spidamine, reserpine, phorbol, a phorbol diester, pioglitazone (Actos™

), MK-886, somatostatin receptor agonist, 506BD, methallylrapamycin, rapamycin, and an isatin Michael acceptor.

8. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 1, wherein the pharmaceutically active moiety is selected from a peptide and an oligonucleotide.

9. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 1, wherein the pharmaceutically active moiety is an apoptosis-inducing peptide.

10. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 9, wherein the apoptosis-inducing peptide comprises an apoptosis-inducing domain of a proapoptotic polypeptide or a variant thereof, wherein the apoptosis-inducing domain of the proapoptotic polypeptide or a variant thereof has apoptosis-inducing activity, and wherein the variant of the apoptosis-inducing domain of the proapoptotic polypeptide has at least 50% sequence identity with the apoptosis-inducing domain.

11. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 10, wherein the apoptosis-inducing peptide is a Bim polypeptide, a BH3 domain of a Bim polypeptide or a variant thereof having apoptosis-inducing activity and having at least 95% sequence identity with the BH3 domain of the Bim polypeptide.

12. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 1, wherein the cell receptor is a sigma-2 receptor, and wherein the targeting moiety is covalently linked to a peptide having an amino acid sequence selected from the group consisting of EIWIAQELRRIGDEFNAYYAR (SEQ ID NO:

1) and

LDPKLMKEEQMSQAQLFTRSFDDGL (SEQ ID NO;

     2).

13. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 12, wherein the targeting moiety comprises a structure

14. A method of treating a cancer, comprising administering to a subject in need of treatment of a cancer an effective amount of the compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof of claim 1.

15. A method of treating a cancer in accordance with claim 14, wherein the targeting moiety is an N-substituted 9-azabicyclo[3.3.1]nonan-3α

-yl phenylcarbamate of structure

16. A method of treating a cancer in accordance with claim 15, wherein the pharmaceutically active moiety is a peptide having apoptosis-inducing activity and is selected from the group consisting of a BH3 domain of a Bim polypeptide, a variant thereof having apoptosis-inducing activity, an apoptosis-inducing domain of a negative regulator of an Akt protein kinase and a variant thereof having apoptosis-inducing activity.

17. A method of treating a cancer in accordance with claim 14, wherein the cancer is a pancreatic cancer.

18. A method of inducing apoptosis in a cell, comprising:

contacting the cell with a compound comprising a) a non-peptide targeting moiety which, in free form, has a molecular weight of less than about 1200 Da and binds a sigma-2 receptor with a dissociation constant K_d of less than about 10<sup>−

7</sup> M, and b) a proapoptotic peptide moiety.

19. A method of inducing apoptosis in accordance with claim 18, wherein the targeting moiety comprises

20. A method of inducing apoptosis in accordance with claim 18, wherein the proapoptotic peptide moiety comprises a sequence selected from the group consisting of EIWIAQELRRIGDEFNAYYAR (SEQ ID NO:

1), a variant thereof having at least 90% sequence similarity, MSQAQLFTRSFDDGL (SEQ ID NO;

     2) and a variant thereof having at least 90% sequence similarity, and wherein the peptide or variant thereof has proapoptotic activity.