# US 9,518,079 B2 · Effective treatment of tumors and cancer with triciribine and related compounds

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- Number: US 9,518,079 B2
- Document ID: US9518079B2
- Status: Granted
- Kind: B2
- Application number: 14/800,286
- Filed: 2015-07-15
- Published: 2015-11-12
- Granted: 2016-12-13
- Earliest claimed: 2004-03-29
- Assignees: University of South Florida
- Applicants: University of South Florida
- Inventors: Jin Q. Cheng; Said M. Sebti
- Web page: https://patentgrep.com/patent/US9518079B2

## CPC

- C07H 17/02: Heterocyclic radicals containing only nitrogen as ring hetero atoms
- A61K 31/7064: containing condensed or non-condensed pyrimidines
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- 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

## Abstract

The inventors have determined, contrary to the prior art and experience, how to successfully use triciribine to treat tumors and cancer by one or a combination of (i) administering triciribine only to patients which according to a diagnostic test described below, exhibit enhanced sensitivity to the drug; (ii) use of a described dosage level that minimizes the toxicity of the drug but yet still exhibits efficacy; or (iii) use of a described dosage regimen that minimizes the toxicity of the drug.

## Claims

### Claim 1

A method for identifying and treating a patient having a tumor or cancer cell with enhanced sensitivity to triciribine (TCN) comprising:
(a) determining whether a patient has a tumor or cancer cell with enhanced sensitivity to triciribine comprising:
(i) obtaining a biological sample of the tumor or cancer cell from the patient;
(ii) measuring the expression level of Akt kinase from the tumor or cancer cell from the patient; and
(iii) comparing the expression level of Akt kinase from the tumor or cancer cell to the expression level in a control tissue,
(b) administering to the patient having a tumor or cancer cell with enhanced sensitivity to triciribine at least one compound of the formula:
wherein each R2′, R3′, and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate; acyl; alkyl; amide, sulfonate ester; sulfonyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate; optionally substituted arylsulfonyl; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′ or R5′ is independently H or mono-, di- or tri-phosphate;
wherein Rx and Ry are independently hydrogen, optionally substituted phosphate; acyl; amide, alkyl; aromatic, polyoxyalkylene, optionally substituted arylsulfonyl; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group; and
R1 and R2 each are independently H, optionally substituted straight chained, branched or cyclic alkyl, alkenyl, or alkynyl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO-aryl or heteroaryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonyl, alkyl sulfonyl, aryl sulfonyl, or aralkyl sulfonyl,
wherein said treatment comprises administering at least 10 mg/m2 of at least one compound by intravenous infusion to cause regression of the tumor or cancer cell.

### Claim 2 (depends on 1)

The method of claim 1, wherein the biological sample is taken from breast, pancreas, ovary, colon, or rectum.

### Claim 3 (depends on 1)

The method of claim 1, wherein a 1.5-fold greater expression of Akt in the tumor or cancer cell compared to a control tissue is indicative of a patient having a tumor or cancer cell with enhanced sensitivity to triciribine.

### Claim 4 (depends on 1)

The method of claim 1, wherein the level of Akt kinase expression is determined by assaying the cancer for the presence of a phosphorylated Akt kinase.

### Claim 5 (depends on 1)

The method of claim 1, wherein the level of Akt kinase expression is determined by assaying the cancer for the presence of a phosphorylated Akt kinase with an antibody.

### Claim 6

A method of treating a tumor or cancer in a patient, wherein the tumor or cancer is of the pancreas, ovary or colon, and wherein the tumor or cancer has enhanced sensitivity to triciribine (TCN) comprising:
administering to the patient at least one compound of the formula:
wherein each R2′, R3′, and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate; acyl; alkyl; amide, sulfonate ester; sulfonyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate; optionally substituted arylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′, and R5′ is independently H or mono-, di- or tri-phosphate;
wherein Rx and Ry are independently hydrogen, optionally substituted phosphate; acyl; amide, alkyl; aromatic, polyoxyalkylene optionally substituted arylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group;
R1 and R2 each are independently H, optionally substituted straight chained, branched or cyclic alkyl, alkenyl, or alkynyl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO-aryl or heteroaryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonyl, alkylsulfonyl, arylsulfonyl, or aralkylsulfonyl; and
wherein at least 10 mg/m2 of the compound is administered by intravenous infusion one time per week.

### Claim 7 (depends on 6)

The method of claim 6, wherein the dosing schedule is repeated at least twice.

### Claim 8 (depends on 6)

The method of claim 6, wherein the dosing schedule is repeated at least 4 times.

### Claim 9

A method for identifying and treating a patient having a tumor or cancer cell with enhanced sensitivity to triciribine (TCN), wherein the tumor or cancer is of the pancreas, ovary or colon, in a mammal comprising:
(a) determining whether a patient has a tumor or cancer cell with enhanced sensitivity to triciribine comprising:
(i) obtaining a biological sample of the tumor or cancer cell from the patient;
(ii) measuring the expression level of Akt kinase from the tumor or cancer cell from the patient; and
(iii) comparing the expression level of Akt kinase from the tumor or cancer cell to the expression level in a control tissue,
wherein a 1.5-fold greater expression of Akt in the tumor or cancer cell compared to a control tissue is indicative of a patient having a tumor or cancer cell with enhanced sensitivity to triciribine; and
(b) administering to the mammal at least one compound selected from the group consisting of:
wherein each R2′, R3′, and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate; acyl; alkyl; amide, sulfonate ester; sulfonyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate; optionally substituted arylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′, and R5′ is independently H or mono-, di- or tri-phosphate;
wherein Rx and Ry are independently hydrogen, optionally substituted phosphate; acyl; amide, alkyl; aromatic, polyoxyalkylene optionally substituted arylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group;
R1 and R2 each are independently H, optionally substituted straight chained, branched or cyclic alkyl, alkenyl, or alkynyl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO-aryl or heteroaryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonyl, alkylsulfonyl, arylsulfonyl, or aralkylsulfonyl; and
wherein at least 10 mg/m2 of the compound is administered over a one-hour intravenous infusion with a dosing regimen of one time per week for three weeks.

### Claim 10 (depends on 9)

The method of claim 9, wherein the dosing cycle is repeated at least twice.

### Claim 11 (depends on 9)

The method of claim 9, wherein the dosing cycle is repeated until regression of the cancer is achieved.

### Claim 12 (depends on 9)

The method of claim 9, wherein the subject has been diagnosed with a carcinoma, sarcoma, lymphoma, leukemia, or myeloma.

### Claim 13 (depends on 9)

The method of claim 9, wherein the mammal is a human.

### Claim 14 (depends on 9)

The method of claim 9, wherein the compound is the compound of Formula IB:

### Claim 15 (depends on 9)

The method of claim 9, wherein the compound is the compound of Formula IIA: