Method and compositions for forming a copper-containing complex and uses thereof

Patent metadata

Field	Value
Publication number	US-2020376006-A1
Application number	US-201816761631-A
Country	US
Kind code	A1
Filing date	Nov 6, 2018
Priority date	Nov 6, 2017
Publication date	Dec 3, 2020
Grant date	—

Abstract

Provided is a method of forming a copper-containing complex, including contacting a sample containing copper with a compound of Formula I:

wherein R is —OH or —O—CH3. Also provided is a method of inhibiting enzymatic activity of a kinase in a sample, including contacting the sample with a compound of Formula I. Further provided is a method of administering to a subject a pharmaceutical composition including a compound of Formula I optionally complexed with copper. Also provided is a pharmaceutical composition including copper complexed with a compound of Formula I.

First claim

1 . A method of forming a copper-containing complex, comprising contacting a sample containing copper with a compound of Formula I:

wherein R is —OH or —O—CH 3 .

2 . (canceled)

3 . The method of claim 1 , wherein said sample containing copper is a biological solution, suspension, tissue or organism.

4 . The method of claim 3 , wherein contacting a sample comprises administering said compound to a subject.

5 . The method of claim 4 , wherein administering said compound reduces a cytotoxic effect of copper.

6 . The method of claim 5 , wherein the subject is a human diagnosed with a disorder that is associated with elevated physiological levels of copper.

7 . The method of claim 6 , wherein the disorder is Wilson's disease.

8 . The method of claim 1 , comprising inhibiting the catalytic activity of an enzyme by forming the copper-containing complex, and the enzyme is selected from the group consisting of pyruvate kinase M (PKM), mitochondrial adenylate kinase 2 (AK2), creatine kinase B (CKB), p21-activated kinase (PAK), TP53-regulating kinase (TP53RK), phosphoglycerate kinase 1 (PGK1), pyridoxal kinase (PDXK), mitochondrial creatine kinase U-type (CKMT1B), mitogen-activated protein kinase kinase (MEK), tyrosine kinase CSK, protein tyrosine phosphatase 1B (PTP1B), and any combination of two or more of the foregoing.

9 . A method of inhibiting enzymatic activity of a kinase in a sample, comprising contacting the sample with a compound of Formula I:

wherein R is —OH or —O—CH 3 , and
wherein the kinase is selected from the group consisting of pyruvate kinase M (PKM), mitochondrial adenylate kinase 2 (AK2), creatine kinase B (CKB), p21-activated kinase (PAK), TP53-regulating kinase (TP53RK), phosphoglycerate kinase 1 (PGK1), pyridoxal kinase (PDXK), mitochondrial creatine kinase U-type (CKMT1B), mitogen-activated protein kinase kinase (MEK), tyrosine kinase CSK, and any combination of two or more of the foregoing.

10 . The method of claim 9 , wherein the sample comprises a subject in need of medical treatment and contacting the sample comprises administering said compound to the subject.

11 . The method of claim 10 , wherein the subject has gastric cancer.

12 . The method of claim 10 wherein the subject has a HER2-negative breast cancer.

13 . The method of claim 12 , wherein the HER2-negative cancer is estrogen-receptor negative cancer, progesterone-receptor negative cancer, or triple-negative breast cancer.

14 . The method of claim 10 , wherein the subject has triple-negative breast cancer.

15 . The method of claim 11 , further comprising administering to said subject AZD6244.

16 . The method of claim 12 , further comprising administering to said subject AZD6244.

17 . The method of claim 16 , wherein the therapeutic effect comprises an inhibition of tumor growth, an inhibition of cancer cell metastasis, a stimulation of cancer cell death, or any combination of two or more of the foregoing.

18 . (canceled)

19 . (canceled)

20 . A method of administering to a subject a pharmaceutical composition comprising copper complexed with a compound of Formula I:

wherein R is —OH or —O—CH 3 .

21 . The method of claim 20 , wherein administering the pharmaceutical composition comprises reducing the subject's Body Mass Index.

22 . The method of claim 20 , wherein administering the pharmaceutical composition comprises enhancing a physiological response to one or more hormones and the one or more hormones are insulin, leptin, or both.

23 . (canceled)

24 . (canceled)

25 . The method of claim 24 , wherein the cancer is triple-negative breast cancer.

26 . The method of claim 23 , further comprising administering to said subject AZD6244.

27 . (canceled)

28 . (canceled)

29 . (canceled)

30 . (canceled)

31 . The method of claim 20 , wherein administering the compound comprises inhibiting activity of protein tyrosine phosphatase 1B (PTP1B) in the subject.

32 . A pharmaceutical composition comprising copper complexed with a compound of Formula I:

wherein R is —OH or —O—CH 3 .

33 . The pharmaceutical composition of claim 32 , further comprising a pharmaceutically acceptable excipient.

Assignees

• Cold Spring Harbor Laboratory
• Depymed Inc

Inventors

• Tonks Nicholas
• Krishnan Navasona
• Grill Andreas
• Sard Howard

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/58 Primary

  containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048}) · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61K31/30

  Copper compounds · CPC title

• C07J43/003 Primary

  not condensed · CPC title