Modular platform for targeted therapeutic delivery

• US 8,143,222 B2
• Filed: 10/22/2008
• Issued: 03/27/2012
• Est. Priority Date: 10/22/2007
• Status: Active Grant

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: McDunn, Jonathan E., Hawkins, William G., Mach, Robert H., Hotchkiss, Richard A.
• Primary Examiner(s): Russel, Jeffrey E
• Application Number:
  US12/255,947
• Publication Number:
  US 20090176705A1
• Time in Patent Office: 1,252 Days
• Field of Search: None
• US Class Current: 514/18.9
• 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 Kd 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 peptidominietic, a protein or a protein domain, and wherein the targeting moiety and the pharmaceutically active moiety are covalently attached, and, wherein the pharmaceutically active moiety is an apoptosis-inducing peptide.

2. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 1, 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.

3. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 2, 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.

4. 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 Kd 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, 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).

5. A compound or a pharmaceutically acceptable salt, prodrug or hydrate thereof in accordance with claim 4, wherein the targeting moiety comprises a structure

6. A method of treating a cancer, comprising administering to a subject in need of treatment of a cancer an effective amount of 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 Kd of less than about 10<sup>−

7</sup> M and is an N-substituted 9-azabicyclo[3.3.1]nonan-3α

-yl phenylcarbamate of structure

7. A method of treating a cancer in accordance with claim 6, wherein the cancer is a pancreatic cancer.

8. 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 Kd of less than about 10<sup>−

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

9. A method of inducing apoptosis in accordance with claim 8, wherein the targeting moiety comprises

10. A method of inducing apoptosis in accordance with claim 8, 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, LDPKLMKEEQMSQAQLFTRSFDDGL (SEQ ID NO;

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