Lipopeptide inhibitors of ras oncoproteins

Abstract

A method of inhibiting Ras activity in a cell comprising introducing a peptide or peptidomimetic into the cell, wherein the peptide or peptidomimetic is derived from or based upon the amino acid sequence of the C-terminal α-helix or hypervariable region (HVR) or a Ras protein.

1 . A method of inhibiting Ras activity in a cell comprising introducing a peptide or peptidomimetic into the cell, whereby activity of Ras is inhibited; wherein the peptide or peptidomimetic comprises:
 (a) the amino acid sequence X 1 YTLVRX 2 X 3 RX 4 X 5  (SEQ ID NO: 5) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (b) the amino acid sequence KTPGX 1 VKIKK (SEQ ID NO: 6) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (c) the amino acid sequence KKSKTK (SEQ ID NO: 7) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (d) the amino acid sequence SGPGX 1 X 2 SX 3 K (SEQ ID NO: 8) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (e) the amino acid sequence GTQGX 1 X 2 GLP (SEQ ID NO: 9) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (f) eight or more contiguous amino acids of the C-terminal α-helix of a Ras protein or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises a total of about 30 or fewer amino acids; or   (g) five or more contiguous amino acids of the hypervariable region (HVR) of a Ras protein or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises a total of about 30 or fewer amino acids.   
     
     
         2 . The method of  claim 1 , wherein the peptide or peptidomimetic is introduced into the cell by contacting the cell with the peptide or peptidomimetic. 
     
     
         3 . The method of  claim 1 , wherein the peptide or peptidomimetic is introduced into the cell by contacting the cell with a nucleic acid encoding the peptide or peptidomimetic, whereby the peptide or peptidomimetic is expressed in the cell. 
     
     
         4 . The method of  claim 1 , wherein the cell is a cancer cell. 
     
     
         5 . The method of  claim 1 , wherein the cell is in a mammal. 
     
     
         6 . The method of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence X 1 YTLVRX 2 X 3 RX 4 X 5  (SEQ ID NO: 5) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids. 
     
     
         7 . The method of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence KTPGX 1 VKIKK (SEQ ID NO: 6) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids. 
     
     
         8 . The method of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence KKSKTK (SEQ ID NO: 7) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids. 
     
     
         9 . The method of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence SGPGX 1 X 2 SX 3 K (SEQ ID NO: 8) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids. 
     
     
         10 . The method of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence GTQGX 1 X 2 GLP (SEQ ID NO: 9) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids. 
     
     
         11 . The method of  claim 1 , wherein the peptide or peptidomimetic comprises eight or more contiguous amino acids of the C-terminal α-helix of a Ras protein or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises a total of about 30 or fewer amino acids. 
     
     
         12 . The method of  claim 1 , wherein the peptide or peptidomimetic comprises five or more contiguous amino acids of the hypervariable region (HVR) of a Ras protein or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises a total of about 30 or fewer amino acids. 
     
     
         19 . The method of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence of any one of SEQ ID NOs: 10-72 or 75-86, or the inverse sequence thereof. 
     
     
         13 . The method of  claim 1 , wherein the peptide or peptidomimetic comprises about 20 or fewer amino acids. 
     
     
         14 . The method of  claim 1 , wherein the peptide or peptidomimetic comprises one or more D-amino acids. 
     
     
         15 . The method of  claim 1 , wherein the peptide or peptidomimetic further comprises a cell-penetrating motif. 
     
     
         16 . The method of  claim 1 , wherein the peptide or peptidomimetic further comprises a terminal fatty acid group, an N-terminal palmitoyl residue, an N-terminal myristoyl residue, an N-terminal lauryl residue, or an N-terminal octanoyl residue. 
     
     
         20 . The method of  claim 1 , wherein the peptide or peptidomimetic interacts with the C-terminal α-helix or Hypervariable Region (HVR) of Ras. 
     
     
         17 . A method for inhibiting the growth or proliferation of a cancer cell comprising administering a peptide or peptidomimetic to the cancer cell, whereby the growth and proliferation of the cancer cell is inhibited; wherein the peptide or peptidomimetic comprises:
 (a) the amino acid sequence X 1 YTLVRX 2 X 3 RX 4 X 5  (SEQ ID NO: 5) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (b) the amino acid sequence KTPGX 1 VKIKK (SEQ ID NO: 6) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (c) the amino acid sequence KKSKTK (SEQ ID NO: 7) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (d) the amino acid sequence SGPGX 1 X 2 SX 3 K (SEQ ID NO: 8) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (e) the amino acid sequence GTQGX 1 X 2 GLP (SEQ ID NO: 9) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (f) eight or more contiguous amino acids of the C-terminal α-helix of a Ras protein or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises a total of about 30 or fewer amino acids; or   (g) five or more contiguous amino acids of the hypervariable region (HVR) of a Ras protein or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises a total of about 30 or fewer amino acids.   
     
     
         18 . A method for treating cancer in a host comprising administering to the host a peptide or peptidomimetic, or nucleic acid encoding a peptide or peptidomimetic, whereby cancer is treated; wherein the peptide or peptidomimetic comprises:
 (a) the amino acid sequence X 1 YTLVRX 2 X 2 RX 4 X 5  (SEQ ID NO: 5) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (b) the amino acid sequence KTPGX 1 VKIKK (SEQ ID NO: 6) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (c) the amino acid sequence KKSKTK (SEQ ID NO: 7) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (d) the amino acid sequence SGPGX 1 X 2 SX 3 K (SEQ ID NO: 8) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (e) the amino acid sequence GTQGX 1 X 2 GLP (SEQ ID NO: 9) or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids;   (f) eight or more contiguous amino acids of the C-terminal α-helix of a Ras protein or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises a total of about 30 or fewer amino acids; or   (g) five or more contiguous amino acids of the hypervariable region (HVR) of a Ras protein or the inverse sequence thereof, wherein the peptide or peptidomimetic comprises a total of about 30 or fewer amino acids.   
     
     
         19 . The method of  claim 18 , wherein the cancer is colon cancer, pancreatic cancer, leukemia, bladder cancer, salivary gland cancer, melanoma, myeloid malignancy, or germ cell tumors.