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US 2013/0296405 A1Published application
Compounds Having Anti-Adhesive Effects on Cancer Cells
AssigneeGeron Corporation
InventorsSergei Gryaznov, Jerry Shay, Woodring Wright
Life of this patent
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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.
Claims33
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′;
- 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 in is 1 to 3;
- and
- (ii) said polynucleoside moiety includes at least one motif selected from GGG and GG(W)1-3GG, containing residues G and/or 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, and
- (d) n is 1 or 2;
- with the proviso that, when said polynucleoside moiety O includes a sequence seven or more nucleobases in length that is complementary to a region of hTR (SEQ ID NO:
- 1), the compound O-(x-L)n is not a telomerase inhibitor.
12 more elements
A method of inhibiting cell adhesion, comprising
- contacting said cells with 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′, 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 and GG(W)1-3GG, containing residues G and/or 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, and
- (d) n is 1 or 2;
- with the proviso that, when said polynucleoside moiety O includes a sequence seven or more nucleobases in length that is complementary to a region of hTR (SEQ ID NO:
- 1), the compound O-(x-L)n is not a telomerase inhibitor.
12 more elements
A method of treating cancer in a patient, by inhibiting adhesion of cancer cells, 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′, 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 and GG(W)1-3GG, containing residues G and/or 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, and
- (d) n is 1 or 2;
- with the proviso that, when said polynucleoside moiety O includes a sequence seven or more nucleobases in length that is complementary to a region of hTR (SEQ ID NO:
- 1), the compound O-(x-L)n is not a telomerase inhibitor.
11 more elements
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′, 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 and GG(W)1-3GG, containing residues G and/or 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, and
- (d) n is 1 or 2;
- with the proviso that, when said polynucleoside moiety O includes a sequence seven or more nucleobases in length that is complementary to a region of hTR (SEQ ID NO:
- 1), the compound O-(x-L)n is not a telomerase inhibitor;
- for use in medicine.
12 more elements
Use 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′, 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 and GG(W)1-3GG, containing residues G and/or 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, and
- (d) n is 1 or 2;
- with the proviso that, when said polynucleoside moiety 0 includes a sequence seven or more nucleobases in length that is complementary to a region of hTR (SEQ ID NO:
- 1), the compound O-(x-L)n is not a telomerase inhibitor;
- for the manufacture of a medicament for treating cancer.
12 more elements
Dependencies are inferred from the claim text.