# US 11,433,086 B2 · Combination of T-cell checkpoint inhibitors with inhibitors of e-selectin or CXCR4, or with heterobifunctional inhibitors of both E-selectin and CXCR4

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- Number: US 11,433,086 B2
- Document ID: US11433086B2
- Status: Granted
- Kind: B2
- Application number: 16/323,685
- Filed: 2017-08-07
- Published: 2019-07-04
- Granted: 2022-09-06
- Earliest claimed: 2016-08-08
- Assignees: GlycoMimetics, Inc.
- Applicants: GlycoMimetics, Inc.
- Inventors: John L. Magnani; William E. Fogler
- Web page: https://patentgrep.com/patent/US11433086B2

## CPC

- A61K 31/7034: attached to a carbocyclic compound, e.g. phloridzin
- A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205)
- A61K 31/395: having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K 31/69: Boron compounds
- A61K 31/702: Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 47/61: the organic macromolecular compound being a polysaccharide or a derivative thereof
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Compositions and methods for the treatment of diseases, disorders, and/or conditions associated with the increased regulatory T lymphocyte cell function, comprising the administration of T-cell checkpoint inhibitors in combination with E-selectin inhibitors, C—X—C Motif Chemokine Receptor 4 (CXCR4) receptor inhibitors, and/or heterobifunctional inhibitors that comprise at least one E-selectin inhibitor linked to at least one CXCR4 receptor inhibitor, are disclosed.

## Claims

### Claim 1

A method for treating a cancer chosen from multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, colorectal cancer, and prostate cancer comprising administering to a subject in need thereof:
(1) an effective amount of pembrolizumab; and
(2) an effective amount of at least one heterobifunctional inhibitor chosen from compounds of Formula (II):
isomers of compounds of Formula (II), tautomers of compounds of Formula (II), and pharmaceutically acceptable salts of any of the foregoing, wherein:
R1 is chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups;
R2 is chosen from —OH, —NH2, —OC(═O)Y1, —NHC(═O)Y1, and —NHC(═O)NHY1 groups, wherein Y1 is chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl, C6-18 aryl, and C1-13 heteroaryl groups;
R3 is chosen from —CN, —CH2CN, and —C(═O)Y2 groups, wherein Y2 is chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, —OZ1, —NHOH, —NHOCH3, —NHCN, and —NZ1Z2 groups, wherein Z1 and Z2, which may be identical or different, are independently chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups, wherein Z1 and Z2 may together form a ring;
R4 is chosen from C3-8 cycloalkyl groups;
R5 is independently chosen from H, halogen, C1-8 alkyl C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups;
n is chosen from integers ranging from 1 to 4; and
Linker is chosen from linker groups.

### Claim 2 (depends on 1)

The method of claim 1, wherein at least one of (1) pembrolizumab and (2) the at least one heterobifunctional inhibitor is in the form of at least one pharmaceutical composition.

### Claim 3 (depends on 1)

The method of claim 1, wherein pembrolizumab is in the form of a first pharmaceutical composition and the at least one heterobifunctional inhibitor is in the form of a second pharmaceutical composition.

### Claim 4 (depends on 2)

The method of claim 2, wherein said at least one pharmaceutical composition further comprises at least one pharmaceutically acceptable ingredient.

### Claim 5 (depends on 1)

The method of claim 1, wherein the at least one heterobifunctional inhibitor is chosen from compounds of Formula (IIa):
isomers of compounds of Formula (IIa), tautomers of compounds of Formula (IIa), and pharmaceutically acceptable salts of any of the foregoing.

### Claim 6 (depends on 1)

The method of claim 1, wherein the at least one heterobifunctional inhibitor is GMI-1359.

### Claim 7 (depends on 1)

The method of claim 1, wherein the subject has received or will receive chemotherapy and/or radiotherapy.

### Claim 8 (depends on 7)

The method of claim 7, wherein the chemotherapy comprises administering an effective amount of bortezomib and/or gemcitabine.

### Claim 9 (depends on 1)

The method of claim 1, wherein Linker is chosen from

### Claim 10 (depends on 1)

The method of claim 1, wherein the at least one heterobifunctional inhibitor is chosen from:
pharmaceutically acceptable salts of any of the foregoing.

### Claim 11 (depends on 1)

The method of claim 1, wherein the at least one heterobifunctional inhibitor is chosen from:
pharmaceutically acceptable salts of any of the foregoing.

### Claim 12 (depends on 1)

The method of claim 1, wherein the at least one heterobifunctional inhibitor is chosen from
pharmaceutically acceptable salts thereof.