US2015218277A1PendingUtilityA1
Inhibitors of the Epidermal Growth Factor Receptor- Heat Shock Protein 90 Binding Interaction
Est. expiryDec 20, 2030(~4.4 yrs left)· nominal 20-yr term from priority
A61K 31/7068A61K 38/00C07K 14/71C07K 2319/95C12N 15/1138A61K 38/08C07K 5/10A61K 31/7088C07K 2319/10A61K 9/0019A61K 38/07C07K 2317/626A61P 35/00A61N 5/10C12N 2310/16A61K 39/39558A61K 2039/505C07K 2317/569C07K 2317/622C07K 7/06C07K 2317/55C07K 16/2863A61K 33/24A61K 33/243
43
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Provided herein are compounds that inhibit a binding interaction between an epidermal growth factor receptor (EGFR) and a heat shock protein 90 (HSP90), as well as compositions, e.g., pharmaceutical compositions, comprising the same, and related kits. In some embodiments, the compound is an antibody or antibody analog, and, in other embodiments, the compound is a peptide or peptide analog. Also provided are methods of using the compounds, including methods of increasing degradation of an EGFR, methods of treating cancer, and methods of sensitizing tumors to radiation therapy.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A composition comprising a compound that inhibits a binding interaction between an epidermal growth factor receptor (EGFR) and a heat shock protein 90 (HSP90).
2 . The composition of claim 1 , wherein the compound is a peptide or peptide analog.
3 . The composition of claim 2 , wherein the peptide analog is a peptoid, or peptidomimetic.
4 . The composition of claim 2 or 3 , wherein the compound comprises 4 to 10 consecutive amino acids of amino acids 688 to 955 of SEQ ID NO: 1.
5 . The composition of claim 4 , wherein the compound comprises 4 to 10 consecutive amino acids from amino acids 761-781 of the EGFR.
6 . The composition of claim 5 , wherein the compound comprises the amino acid sequence DNPH (SEQ ID NO: 13) or RLLGIC (SEQ ID NO: 14).
7 . The composition of claim 6 , wherein the compound comprises the amino acid sequence SVDNPH (SEQ ID NO: 15), or SVDNPHV (SEQ ID NO: 16), or SVDNPHVX (SEQ ID NO: 17), wherein X is C, S, G, V, or A.
8 . The composition of claim 2 or 3 , wherein the compound comprises an amino acid sequence of SVDNPH (SEQ ID NO: 15) with up to two amino acid substitutions.
9 . The composition of claim 8 , wherein the amino acid substitution(s) occur(s) at one or two of the positions 1, 3, and 5 of SVDNPH (SEQ ID NO: 15).
10 . The composition of claim 9 , wherein the compound comprises S, D, I, or A at position 1 of SEQ ID NO: 15.
11 . The composition of claim 9 or 10 , wherein the compound comprises D, A, or G at position 3 of SEQ ID NO: 15.
12 . The composition of any of claims 8 to 11 , wherein the analog comprises P or G at position 5 of SEQ ID NO: 15.
13 . The composition of any of claims 8 to 12 , wherein the peptide or peptidomimetic comprises an amino acid sequence selected from the group consisting of:
a.
(SEQ ID NO: 25)
AVDNPH,
b.
(SEQ ID NO: 26)
DVDNPH,
c.
(SEQ ID NO: 27)
IVDNPH,
d.
(SEQ ID NO: 28)
SVGNPH,
e.
(SEQ ID NO: 29)
SVDNGH,
and
f.
(SEQ ID NO: 30)
SVAAPH.
14 . The composition of any of claims 2 to 13 , comprising an intramolecular bridge which covalently links the side chains of two amino acids of the compound.
15 . The composition of claim 14 , wherein the two amino acids are separated by 3, 4, or 5 amino acids in the amino acid sequence of the compound.
16 . The composition of claim 14 or 15 , wherein the intramolecular bridge is a disulfide bridge, a dithioether bridge, a carba analog bridge, or a lactam bridge.
17 . The composition of claim 16 , wherein the dithioether comprises the structure —S(CH 2 ) n S—, wherein n is 1, 2, 3, 4, or 5.
18 . The composition of claim 16 , wherein the carba analog bridge comprises a C3 to C10 alkyl chain.
19 . The composition of claim 16 , wherein the lactam is formed between the side chains of an amino acid of Formula I and an amino acid of Formula II.
20 . The composition of claim 19 , wherein the amino acid of Formula I is Lys or Orn
21 . The composition of claim 19 or 20 , wherein the amino acid of Formula II is Asp or Glu.
22 . The composition of any of claims 14 to 21 , comprising the amino acid sequence XDNPHX (SEQ ID NO: 32), wherein the side chains of the amino acids at positions 1 and 6 are covalently linked by the intramolecular bridge.
23 . The composition of claim 22 , wherein each of the amino acids at positions 1 and 6 is Cys.
24 . The composition of claim 23 , wherein the side chains of the amino acids at positions 1 and 6 are linked by a disulfide bond or a dithioether.
25 . The composition of 22 , wherein the intramolecular bridge is a lactam and one of the amino acids at positions 1 and 6 is an amino acid of Formula I and the other amino acid is an amino acid of Formula II.
26 . The composition of any of claims 22 to 25 , comprising the amino acid sequence SXDNPHXX (SEQ ID NO: 33), wherein the X at position 8 is C, S, G, V, or A.
27 . The composition of any of claims 2 to 26 , wherein the first amino acid of the peptide or peptide analog is acetylated.
28 . The composition of any of claims 2 to 27 , wherein the last amino acid of the peptide or peptide analog is amidated.
29 . The composition of any of claims 2 to 28 , wherein the peptide or peptide analog is an 8-mer.
30 . The composition of any of claims 2 to 29 , wherein the peptide or peptide analog is fused to a cell penetrating peptide (CPP).
31 . The composition of claim 30 , wherein the CPP comprises the amino acid sequence YGRKKRRQRRR (SEQ ID NO: 31).
32 . The composition of any of claims 2 to 31 , comprising a peptide delivery agent.
33 . The composition of claim 1 , wherein the compound is an antibody, or an antigen binding fragment thereof, or an aptamer.
34 . The composition of claim 33 , wherein the antigen binding fragment is a fab, f(ab) 2 ′, fab 3 , scFv, diabody, triabody, tetrabody, minibody, or single-domain antibody.
35 . The composition of any of claim 1 , 33 or 34 , wherein the compound binds to an epitope within amino acids 688 to 955 of EGFR (SEQ ID NO: 1).
36 . The composition of claim 35 , wherein the compound binds to an epitope within amino acids 761-781 of the EGFR sequence (SEQ ID NO: 1).
37 . The composition of claim 36 , wherein the compound binds to an epitope within amino acids 768-773 of the SEQ ID NO: 1, amino acids 768-775 of SEQ ID NO: 1, or amino acids 776-781 of SEQ ID NO: 1.
38 . The composition of claim 37 , wherein the epitope comprises the amino acid sequence DNPH (SEQ ID NO: 13) or RLLGIC (SEQ ID NO: 14).
39 . The composition of claim 38 , wherein the epitope comprises the amino acid sequence SVDNPH (SEQ ID NO: 15), or SVDNPHV (SEQ ID NO: 16), SVDNPHVX (SEQ ID NO: 17), wherein X is C, S, G, V, or A.
40 . The composition of any of the preceding claims, comprising a pharmaceutically acceptable carrier, diluents, or excipient.
41 . The composition of claim 40 , formulated for injection into an animal or human.
42 . A method of treating cancer in a subject comprising administering to the subject a composition of claim 40 or 41 in an amount effective to treat the cancer.
43 . The method of claim 42 , wherein the cancer is characterized by overexpression of EGFR or expression of a mutant EGFR.
44 . The method of claim 43 , wherein the mutant EGFR is a T790M EGFR mutant, EGFRvIII mutant, or a L858R EGFR mutant.
45 . The method of any of claims 42 to 44 , wherein the cancer is resistant to treatment with a tyrosine kinase inhibitor or a monoclonal antibody.
46 . The method of claim 45 , wherein the tyrosine kinase inhibitor is erlotinib or gefitinib, or wherein the monoclonal antibody is cetuximab or panitumumab.
47 . The method of any of claims 42 to 46 , wherein the cancer is a lung cancer, head and neck cancer, cervical cancer, glioblastoma, colorectal cancer, breast.
48 . The method of any of claims 42 to 47 , comprising administering to the subject radiation therapy or chemotherapy.
49 . The method of claim 48 , wherein the chemotherapy comprises cisplatin and/or gemcitabine administration.
50 . A method of sensitizing tumors to radiation therapy, chemotherapy, or a combination thereof, in a subject, comprising administering to the subject a composition of any of claims 1 to 29 in an amount effective to sensitize the tumors to the therapy.
51 . The method of claim 50 , wherein the composition is administered to the subject prior to administration of the radiation therapy and/or chemotherapy.
52 . The method of claim 51 , wherein the composition is administered to the subject at the same time as the radiation therapy and/or chemotherapy.
53 . A method of increasing degradation of an EGFR in a cell, comprising contacting the cell with a composition of any of claims 1 to 41 in an amount effective to increase degradation.
54 . A kit comprising the composition of any of claims 1 to 41 in combination with an agent used in radiation therapy or chemotherapy.
55 . The composition of claim 40 or 41 for treating cancer in a subject.
56 . The composition of claim 55 , wherein the cancer is characterized by overexpression of EGFR or expression of a mutant EGFR.
57 . The composition of claim 56 , wherein the mutant EGFR is a T790M EGFR mutant, EGFRvIII mutant, or a L858R EGFR mutant.
58 . The composition of any of claims 55 to 57 , wherein the cancer is resistant to treatment with a tyrosine kinase inhibitor or a monoclonal antibody.
59 . The composition of claim 58 , wherein the tyrosine kinase inhibitor is erlotinib or gefitinib, or wherein the monoclonal antibody is cetuximab or panitumumab.
60 . The composition of any of claims 55 to 59 , wherein the cancer is a lung cancer, head and neck cancer, cervical cancer, glioblastoma, colorectal cancer, breast.
61 . The composition of any of claims 1 to 41 for sensitizing tumors to radiation therapy, chemotherapy, or a combination thereof, in a subject.
62 . The composition of claim 61 , wherein the composition is administered to the subject prior to administration of the radiation therapy and/or chemotherapy.
63 . The composition of claim 61 , wherein the composition is administered to the subject at the same time as the radiation therapy and/or chemotherapy.
64 . The composition of any of claims 1 to 41 for increasing degradation of an EGFR in a cell in a subject.Join the waitlist — get patent alerts
Track US2015218277A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.