Lipopeptide inhibitors of RAS oncoproteins
Inventors
Tarasova, Nadya I. • Tarasov, Sergey G. • Gaponenko, Vadim • Kates, Joseph • Ivanova, Alla • Dean, Michael C.
Assignees
1058638 Bc Ltd • Vanderbilt University • University of Illinois System • US Department of Health and Human Services
Publication Number
US-9328142-B2
Publication Date
2016-05-03
Expiration Date
2032-05-25
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The invention provides a peptide or peptidomimetic that is derived from or based upon the amino acid sequence of the C-terminal α-helix or hypervariable region (HVR) or a Ras protein, a nucleic acid encoding the peptide or peptidomimetic, and methods employing the same.
Core Innovation
The invention provides peptides or peptidomimetics derived from or based upon the amino acid sequences of the C-terminal α-helix or the hypervariable region (HVR) of Ras proteins. These peptides or peptidomimetics generally comprise about 30 or fewer amino acids and include specific sequences such as SEQ ID NOs: 10-46, 66-68, 69-72, and variations thereof. The peptides can inhibit Ras activity by various mechanisms including binding to Ras or its targets, interfering with Ras multimerization or membrane binding, and may include cell penetrating motifs or lipid modifications to enhance membrane anchoring and cellular uptake.
Ras proteins are small GTPases that act as signal transducers regulating essential cellular functions like survival, proliferation, and cytoskeletal organization. In their oncogenic mutated form, Ras proteins are constitutively active, leading to uncontrolled signaling and cancer progression. Despite their central role in oncogenesis, there has been no selective, specific inhibitor of the Ras pathway available clinically, and Ras proteins have been considered non-druggable targets. The invention addresses this need by providing inhibitors based on peptide sequences from Ras protein regions that interfere with Ras activity, offering a novel approach to inhibit Ras signaling and cancer cell growth.
Claims Coverage
The claims present two independent claims directed to peptides or peptidomimetics derived from specific amino acid sequences of Ras protein regions, with various modifications to enhance functionality and delivery.
Peptides or peptidomimetics comprising specific Ras-derived sequences
A peptide or peptidomimetic comprising the amino acid sequence of any one of SEQ ID NOs: 10-46 or 75-84, or the inverse sequence thereof, consisting of about 30 or fewer amino acids.
Peptides or peptidomimetics comprising inverse sequences of C-terminal α-helix of Ras
A peptide or peptidomimetic comprising the inverse sequence of the amino acid sequence of any one of SEQ ID NOs: 66, 67, or 68, wherein the peptide or peptidomimetic comprises about 30 or fewer amino acids.
The claims focus on peptides or peptidomimetics derived from the C-terminal α-helix or HVR sequences of Ras proteins, comprising up to about 30 amino acids, including retro-inverso and D-amino acid modifications, and compositions and methods for treating cancer using these peptides.
Stated Advantages
The peptide or peptidomimetic inhibitors exhibit potent inhibition of Ras activity, resulting in the selective inhibition of growth and proliferation of cancer cells.
Lipidation and small peptide size enhance cellular uptake, membrane anchoring, and biological efficacy of the inhibitors.
The inhibitors demonstrate effectiveness against a range of Ras-mutated cancer cell lines and suppress tumor growth in animal models.
Documented Applications
Inhibiting the activity of Ras proteins in cancer cells to reduce tumor cell growth and proliferation.
Treating various cancers including breast cancer, lung cancer, ovarian cancer, prostate cancer, leukemia, pancreatic cancer, colorectal cancer, bladder cancer, salivary gland cancer, myeloid malignancies, germ cell tumors, and melanoma.
Potential use in treating diseases mediated by Ras activity including Costello syndrome, Noonan syndrome, and various autoimmune diseases.
Interested in licensing this patent?