Ras inhibitory peptides and uses thereof

1. A peptide comprising a sequence of:

(SEQ ID NO: 13)

X- 6 X- 5 X- 4 X- 3 X- 2 X- 1 X 1 PX 3 X 4 PX 6 X 7 PGX 10 X 11 AX 13 X 14 X 15 X 16 LX 18

X 19 X 20 X 21 X 22 X 23 LX 25 X 26 YLX 29 X 30 X 31 X 32 ,

wherein X 3 and X 4 are each independently a neutral or charged amino acid;

X 6 is a charged amino acid or an amino acid capable of cross-linking the peptide with another peptide;

X 7 is Tyr, His, or an amino acid capable of cross-linking the peptide with another peptide;

X 10 is Pro, charged amino acid, or an amino acid capable of cross-linking the peptide with another peptide;

X 11 is Ala, Ser, neutral or charged amino acid or an amino acid capable of cross-linking the peptide with another peptide;

X 13 is Ser, Pro, Thr, or an amino acid capable of cross-linking the peptide with another peptide;

X 14 is Ile, Glu, Val, Leu, or an amino acid capable of cross-linking the peptide with another peptide;

X 15 is Glu, Lys, Arg, Ala, Ser, Asp, Gln, or Gly;

X 16 is Asp, Glu, Gln, Ala, or Ser;

X 18 is an aromatic or hydrophobic amino acid;

X 19 is Glu, Lys, Leu, Met, His, Asp, Gln, Ala, Ser, Trp, or Arg;

X 20 is Tyr or Phe;

X 21 is Gln, Tyr, Phe, Trp, His, or an amino acid with a cyclohexyl side chain, wherein Tyr, Phe, Trp, cyclohexyl side chain can be substituted with one or more fluorines;

X 22 is Ala, Gln, Trp, Leu, Tyr, Gly, Ser, Val, or Asn;

X 23 is Arg, Asp, Leu, or Ala;

X 25 is Gln, Tyr, Phe, Trp, His, Asp, or an amino acid with a cyclohexyl side chain, wherein Tyr, Phe, Trp, cyclohexyl side chain can be substituted with one or more fluorines;

X 26 is Asn, Ala, Leu, Arg, Phe, Ile, His, or Gln;

X 29 is Ala, Leu, Glu, Asn, Gln, Tyr, Phe, Trp, His, or an amino acid with a cyclohexyl side chain, wherein Tyr, Phe, Trp, cyclohexyl side chain can be substituted with one or more fluorines;

X 30 is Ala, Arg or Val;

X 31 is V or an amino acid capable of cross-linking the peptide with another peptide;

X 32 is V, Ala, Arg, Ser, or an amino acid capable of cross-linking the peptide with another peptide;

X 6 to X 1 are not present; and

wherein the peptide comprises one to two amino acids cross-linking the peptide with another peptide.

2. The peptide of claim 1 , wherein the peptide is a first peptide that associates with a second peptide to form a peptide dimer that binds to a target protein, wherein the target protein is Ras, a Ras mutant, Myc/Max, RalA, Beta catenin, YAP/TEAD, or NEMO/IκB kinase.

3. A method of treating a disease or condition associated with Ras in a subject in need thereof comprising administering a peptide of claim 1 to the subject.

4. The method of claim 3 , wherein the disease associated with Ras is a proliferative disease.

5. The method of claim 3 , wherein the proliferative disease is cancer.

6. The method of claim 3 , wherein the disease associated with Ras is CFC syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, Legius syndrome, Neurofibromatosis type 1, Noonan syndrome, or Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome).

7. A host cell comprising a peptide of claim 1 .

8. A peptide dimer comprising a first peptide associated with a second peptide, wherein the first and second peptides each independently comprise a peptide sequence of:

(SEQ ID NO: 13)

X- 6 X- 5 X- 4 X- 3 X- 2 X- 1 X 1 PX 3 X 4 PX 6 X 7 PGX 10 X 11 AX 13 X 14 X 15 X 16 LX 18

X 19 X 20 X 21 X 22 X 23 LX 25 X 26 YLX 29 X 30 X 31 X 32 ,

wherein X 3 and X 4 are each independently a neutral or charged amino acid;

X 6 is a charged amino acid or an amino acid capable of cross-linking the peptide with another peptide;

X 7 is Tyr, His, or an amino acid capable of cross-linking the peptide with another peptide;

X 10 is Pro, charged amino acid, or an amino acid capable of cross-linking the peptide with another peptide;

X 11 is Ala, Ser, neutral or charged amino acid or an amino acid capable of cross-linking the peptide with another peptide;

X 13 is Ser, Pro, Thr, or an amino acid capable of cross-linking the peptide with another peptide;

X 14 is Ile, Glu, Val, Leu, or an amino acid capable of cross-linking the peptide with another peptide;

X 15 is Glu, Lys, Arg, Ala, Ser, Asp, Gln, or Gly;

X 16 is Asp, Glu, Gln, Ala, or Ser;

X 18 is an aromatic or hydrophobic amino acid;

X 19 is Glu, Lys, Leu, Met, His, Asp, Gln, Ala, Ser, Trp, or Arg;

X 20 is Tyr or Phe;

X 21 is Gln, Tyr, Phe, Trp, His, or an amino acid with a cyclohexyl side chain, wherein Tyr, Phe, Trp, cyclohexyl side chain can be substituted with one or more fluorines;

X 22 is Ala, Gln, Trp, Leu, Tyr, Gly, Ser, Val, or Asn;

X 23 is Arg, Asp, Leu, or Ala;

X 25 is Gln, Tyr, Phe, Trp, His, Asp, or an amino acid with a cyclohexyl side chain, wherein Tyr, Phe, Trp, cyclohexyl side chain can be substituted with one or more fluorines;

X 26 is Asn, Ala, Leu, Arg, Phe, Ile, His, or Gln;

X 29 is Ala, Leu, Glu, Asn, Gln, Tyr, Phe, Trp, His, or an amino acid with a cyclohexyl side chain, wherein Tyr, Phe, Trp, cyclohexyl side chain can be substituted with one or more fluorines;

X 30 is Ala, Arg or Val;

X 31 is V or an amino acid capable of cross-linking the peptide with another peptide;

X 32 is V, Ala, Arg, Ser, or an amino acid capable of cross-linking the peptide with another peptide;

X −6 to X 1 are not present; and

wherein the first and second peptides each comprise one to two amino acids cross-linking the peptides.

9. The peptide dimer of claim 8 , wherein the peptide dimer is a homodimer.

10. The peptide dimer of claim 8 , wherein the peptide dimer is a heterodimer.