Reprogramming urokinase into an antibody-recruiting anticancer agent

Patent metadata

Field	Value
Publication number	US-2019359966-A1
Application number	US-201816149299-A
Country	US
Kind code	A1
Filing date	Oct 2, 2018
Priority date	Nov 11, 2011
Publication date	Nov 28, 2019
Grant date	—

Abstract

The present invention relates to chimeric (preferably, bifunctional) compounds, compositions comprising those compounds and methods of treating cancer in a patient or subject, especially including metastatic cancer where cancer cells exhibit overexpression (heightened expression) of cell surface urokinase-type plasminogen activator receptor (urokinase receptor) compared to normal (non-cancerous) cells. The compounds preferably covalently bind to the urokinase receptor and recruit native antibodies of the patient or subject where the antibodies can selectively degrade and/or deactivate targeted cancer cells through antibody-dependent cellular phagocytosis and/or antibody-dependent cellular cytotoxicity (ADCC) against a large number and variety of cancers, thus providing cancer cell death and/or an inhibition of growth, elaboration and/or metastasis of the cancer, including remission and cure of the patient's cancer.

First claim

1 . A compound according to the chemical formula:

Where

is a moiety which non-covalent or covalently binds to an active site of urokinase-type plasminogen activator (uPA);

is an antibody binding moiety comprising a hapten which is capable of binding to an antibody in said patient or subject;
L1 is a linker molecule which chemically links

to CT, L2 or

in said compound;
L2 is a linker molecule which chemically links

to CT, L1 or

in a molecule;
CT is a bond or a connector molecule which links L1 and/or L2 to

and/or;

Each j is independently 0, 1, 2, 3, 4 or 5;
Each k is independently 0, 1, 2, 3, 4 or 5, with the proviso that k and/or j are other than 0 when CT is a bond; and
Each m and n is independently an integer from 1 to 15, or
a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

2 . The compound according to claim 1 which further comprises urokinase-type plasminogen activator (uPA) bound to said

group.

3 . (canceled)

4 . The compound according to claim 1 wherein

is a group according to the chemical formula:

Where T is a group R e group or an amino acid group according to the chemical structure:

R AA is a sidechain of an amino acid;
R e is H or an electrophilic group which is reactive with a nucleophile in the active site of uPA to produce a covalent bond;
p1 is an integer from 0 to 25 and
Each (AA) is independently a single amino acid residue, or
a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

5 . The compound according to claim 4 wherein R e is an electrophilic group according to the chemical formula:

Where X e is O, S, or N—R Xe ;
R Xe is H or a C 1 -C 3 alkyl or alkanol group;
R P1 is any group which forms a stable linkage with phosphorous in the phosphonate moiety;
R P2 is a halogen (preferably F);
Each e is independently 0, 1, 2, 3, 4, 5 or 6;
Each f is independently 0 or 1 (often 0); and
Each g is 0, 1, 2, 3, 4, 5 or 6 (often 1);
Each h is independently 0 or 1; and
Each q is independently 1, 2, 3, 4, 5, or 6, or
a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof.

6 . (canceled)

7 . (canceled)

8 . The compound according to claim 4 wherein p 1 is 2 and each (AA) is an amino acid residue independently selected from the group consisting of glycine, alanine, leucine, isoleucine and threonine, glutamic acid, aspartic acid, serine and lysine.

9 . (canceled)

10 . (canceled)

11 . The compound according to claim 4 wherein R e is

Where e, f and h are 0.

12 . (canceled)

12 . (canceled)

13 . (canceled)

14 . (canceled)

15 . A compound according to claim 14 wherein R e is an electrophilic group according to the chemical structure:

Where X e is O, S, or N—R Xe ;
R Xe is H or a C 1 -C 3 alkyl or alkanol group;
R P1 is any group which forms a stable linkage with phosphorous in the phosphonate moiety;
R P2 is a halogen (preferably F);
Each e is independently 0, 1, 2, 3, 4, 5 or 6;
Each f is independently 0 or 1 (often 0); and
Each g is 0, 1, 2, 3, 4, 5 or 6 (often 1);
Each h is independently 0 or 1; and
Each q is independently 1, 2, 3, 4, 5, or 6, or
a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof.

16 . A compound according to claim 1 wherein said

group is a hapten group according to the chemical formula:

Where X″ is O, CH 2 , NR 1 , S; and
R 1 is H, a C 1 -C 3 alkyl group or a —C(O)(C 1 -C 3 ) group; or

Where X b is a bond, O, CH 2 or NR 1 or S; and
R 1 is the same as above; or
a group according to the chemical structure:

Where R N02 is a nitro group or a dinitrophenyl group optionally linked through CH 2 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;
a dinitrophenyl group according to the chemical structure:

Where Y′ is H or NO 2 (preferably H);
X is O, CH 2 , NR 1 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O; and
R 1 is H, a C 1 -C 3 alkyl group, or a —C(O)(C 1 -C 3 ) group; or
a fluorescein group according to the chemical structure:

17 . (canceled)

18 . A compound according to claim 1 wherein L 1 and/or L 2 is a group according to the chemical structure:

or a
a group according to the chemical structure:

or
a polypropylene glycol or polypropylene-co-polyethylene glycol linker containing between 1 and 100 alkyleneglycol units;
Where R a is H, C 1 -C 3 alkyl or alkanol or forms a cyclic ring with R 3 when R 3 is a sidechain of proline and R 3 is a side chain derived from an amino acid;
Each m is independently an integer from 1 to 100; and
Each n is independently an integer from 1 to 100.

19 . (

Assignees

• Univ Yale

Inventors

• Spiegel David A
• Jakobsche Charles E

Classifications

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K38/05

  Dipeptides · CPC title

• C07K5/06026

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• C12N9/96 Primary

  Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates · CPC title