# US 8,785,409 B2 · Compounds having anti-adhesive effects on cancer cells

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- Number: US 8,785,409 B2
- Document ID: US8785409B2
- Status: Granted
- Kind: B2
- Application number: 12/524,844
- Filed: 2008-01-30
- Published: 2010-05-06
- Granted: 2014-07-22
- Earliest claimed: 2007-01-30
- Assignees: Geron Corporation; Board of Regents, The University of Texas System
- Applicants: Sergei M. Gryaznov; Jerry W. Shay; Woodring Wright
- Inventors: Sergei M. Gryaznov; Jerry W. Shay; Woodring Wright
- Web page: https://patentgrep.com/patent/US8785409B2

## CPC

- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- A61K 47/543: {Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine}
- C07H 21/04: with deoxyribosyl as saccharide radical
- 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)

## Abstract

Compounds of the form O-(x-L)n, where O is an oligonucleoside having at least a plurality of N3′→P5′ thiophosphoramidate (NPS) internucleoside linkages, a conjugated lipid moiety L, and at least one G-rich sequence motif as described, are effective to morphologically alter and reduce adhesion of cancer cells.

## Claims

### Claim 1

A compound having a structure represented by o-(x-L)n, where
(a) o is a polynucleoside moiety comprising a sequence of nucleosides and linkage moieties, wherein
(i) at least 50% of said linkage moieties are selected from: 3′-NH—P(O)(S−)-5′; 3′-NH—P(O)(S−)—{OR}m—Y—P(O)(S−)-5′; and 3′-Y—R—O—P(O)(S−)-5′;
and at least 75% of internucleoside linkage moieties are selected from 3′-NH—P(O)(S−)-5′ and 3′-NH—P(O)(S−)—{OR}m—Y—P(O)(S−)-5′;
where Y is NH or O; R is a stable linear chain two to six atoms in length having bonds selected from alkyl, alkenyl, ether, thioether, and amino; and m is 1 to 3;
and
(ii) said polynucleoside moiety includes at least one motif selected from GGG, GGWGG, and GGWWGG, containing residues selected from G and W, where G is guanosine and W is a nucleoside or the moiety —OR—, where R is as defined above, and the inter-residue linkages within said motif are N3′→P5′ thiophosphoramidate (3′-NH—P(O)(S−)-5′) or phosphorothioate (3′-O—P(O)(S−)-5′) linkages;
(b) x is an optional linker group,
(c) L is a lipid moiety comprising a linear hydrocarbon moiety at least 12 carbon atoms in length, and
(d) n is 1 or 2;
wherein the compound o-(x-L)n is not a telomerase inhibitor.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Y is NH.

### Claim 3 (depends on 1)

The compound of claim 1, wherein m is 1.

### Claim 4 (depends on 1)

The compound of claim 1, wherein at least 85% of said internucleoside linkage moieties are selected from 3′-NH—P(O)(S−)-5′ (NPS) and 3′-NH—P(O)(S−)—{OR}m—Y—P(O)(S−)-5′, where m is 1.

### Claim 5 (depends on 1)

The compound of claim 1, wherein said inter-residue linkages are 3′-NH—P(O)(S−)-5′ (NPS) linkages.

### Claim 6 (depends on 1)

The compound of claim 1, wherein all of said internucleoside linkage moieties are selected from 3′-NH—P(O)(S−)-5′ (NPS) linkages and 3′-NH—P(O)(S−)—{OR}m—Y—P(O)(S−)-5′ linkages, where m is 1.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R is a stable linear chain three to five atoms in length having bonds selected from alkyl and ether linkages.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R is —(CH2)n—, where n is 3 to 5.

### Claim 9 (depends on 1)

The compound of claim 1, wherein the sum of nucleosides and groups —OR— in the polynucleoside moiety o is from 5 to about 30.

### Claim 10 (depends on 9)

The compound of claim 9, wherein the sum of nucleosides and groups —OR— in the polynucleoside moiety o is from 7 to about 15.

### Claim 11 (depends on 9)

The compound of claim 9, wherein the lipid L is a saturated or monounsaturated hydrocarbon.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the ratio of nucleosides to groups —OR— in the polynucleoside moiety o is 1:1 or greater.

### Claim 13 (depends on 1)

The compound of claim 1, wherein o contains a sequence motif of at least three consecutive guanosine (G) nucleosides directly linked by NPS linkages.

### Claim 14 (depends on 1)

The compound of claim 1, wherein o contains a sequence motif GG(W)1-3GG, where G is guanosine and W is a nucleoside, and the linkages within said motif are N3→P5′ thiophosphoramidate (NPS) linkages.

### Claim 15 (depends on 1)

The compound of claim 1, wherein the lipid L is selected from a linear hydrocarbon, a fatty acid, and a fatty acid derivative, and is attached to the 3′ or 5′ terminus of said oligonucleoside.

### Claim 16 (depends on 15)

The compound of claim 15, wherein the lipid L is a C12 to C24 linear hydrocarbon.

### Claim 17 (depends on 15)

The compound of claim 15, wherein the lipid L is a palmitic or oleic acid derivative and is attached to said terminus via a glycerol or aminoglycerol linker.

### Claim 18 (depends on 1)

The compound of claim 1, containing at least one linkage 3′-NH—P(O)(S−)—O—R—Y—P(O)(S−)-5′, where Y is NH or O, and R is a stable linear chain two to six atoms in length having bonds selected from alkyl, alkenyl, ether, thioether, and amino.

### Claim 19 (depends on 18)

The compound of claim 18, where R is —(CH2)3—.

### Claim 20 (depends on 19)

A compound in accordance with claim 19, wherein said compound is GRN163L A/Link.

### Claim 21 (depends on 1)

A pharmaceutical composition comprising a compound as recited in claim 1 and a pharmaceutically acceptable carrier.

### Claim 22

A method of treating cancer in a patient, by inhibiting adhesion of metastases comprising administering to the patient an effective amount of a compound having a structure represented by o-(x-L)n, where
(a) o is a polynucleoside moiety comprising a sequence of nucleosides and linkage moieties, wherein
(i) at least 50% of said linkage moieties are selected from: 3′NH—P(O)(S−)-5′; 3′-NH—P(O)(S−)—{OR}m—Y—P(O)(S−)-5′; and 3′-Y—R—O—P(O)(S−)-5′, and at least 75% of the internucleoside linkage moieties are selected from 3′-NH—P(O)(S−)-5′ and 3′-NH—P(O)(S−)—{OR}m—Y—P(O)(S−)-5′; where Y is NH or O; R is a stable linear chain two to six atoms in length having bonds selected from alkyl, alkenyl, ether, thioether, and amino; and m is 1 to 3; and
(ii) said sequence includes at least one motif selected from GGG, GGWGG, and GGWWGG, containing residues selected from G and W, where G is guanosine and W is a nucleoside or the moiety —O—R—, where R is as defined above, and the inter-residue linkages within said motif are N3′→P5′ thiophosphoramidate (3′ NH—P(O)(S−)-5′) or phosphorothioate (3′-O—P(O)(S−)-5′) linkages;
(b) x is an optional linker group,
(c) L is a lipid moiety comprising a linear hydrocarbon moiety at least 12 carbon atoms in length, and
(d) n is 1 or 2;
wherein the compound o-(x-L)n is not a telomerase inhibitor,
wherein, subsequent to the administering step, treatment is effected.

### Claim 23 (depends on 22)

The method of claim 22, wherein said administering accompanies tumor biopsy or tumor-reductive surgery.