# US 10,500,288 B2 · Cytotoxic HEXIM1 peptides and uses thereof

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- Number: US 10,500,288 B2
- Document ID: US10500288B2
- Status: Granted
- Kind: B2
- Application number: 15/555,482
- Filed: 2016-03-03
- Published: 2018-08-30
- Granted: 2019-12-10
- Earliest claimed: 2015-03-04
- Assignees: Agency for Science, Technology and Research
- Applicants: Agency for Science, Technology and Research
- Inventors: Sheng-Hao Chao
- Web page: https://patentgrep.com/patent/US10500288B2

## CPC

- A61K 47/6931: {the material constituting the nanoparticle being a polymer}
- A61K 38/04: Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof ({enzyme inhibitors A61K38/005;} gastrins {A61K38/2207}, somatostatins A61K38/31, melanotropins A61K38/34 {; protease inhibitors A61K38/55})
- A61K 47/66: the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 14/00: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K 14/4703: {Inhibitors; Suppressors}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2039/572: {cytotoxic response}
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 35/00: Antineoplastic agents
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are isolated cytotoxic peptides having similar sequences as the basic region (BR) of Hexamethylene Bisacetamide Inducible Protein 1 (HEXIM1). Preferred embodiments include QLGKKKHRRRPSKKKRHW (SEQ ID No: 3). QLGRRRHRRRPSRRRRHW (SEQ ID No: 4) and QLGKKILAARPSKKKRHW (SEQ ID No: 5). Also encompassed are isolated nucleic acid molecules encoding for the claimed peptides, vectors comprising the isolated nucleic acids, compositions comprising peptides conjugated to cell-targeting or penetrating peptides or antibodies, nucleic acid molecules or vectors expressing conjugates thereof; methods of treating or preventing diseases or conditions, including cancers and obesity as well as a method of eliminating undifferentiated stem cells.

## Claims

### Claim 1

A recombinant peptide comprising a cytotoxic peptide and an internalizing peptide, wherein the cytotoxic peptide is conjugated to the internalizing peptide, and wherein the cytotoxic peptide is represented by the consensus sequence Q1-L2-G3-X4-X5-X6-X7-X8-X9-R10-P11-S12-X13-X14-X15-R16-H17-W18 (SEQ ID NO: 36),
wherein,
i) each of X4, X5, and X6 is any amino acid;
ii) X7 is histidine or leucine;
iii) X8 and X9 are independently K or R or H or A; and
iv) X13, X14 and X15 are independently K or R or H;
and, wherein the internalizing peptide is a cancer cell-targeting peptide selected from the group consisting of arginine-glycine-aspartic acid (RGD), asparagine-glycine-arginine (NGR), TCP-1 phage peptide (TCP-1) and any one of the peptides of SEQ ID Nos: 8-11, 64-789 and 795-798.

### Claim 2 (depends on 1)

The recombinant peptide of claim 1, wherein
v) X8 and X9 are the same, and are K or R or H or A; and
vi) X13, X14 and X15 are the same, and are K or R or H.

### Claim 3 (depends on 1)

The recombinant peptide of claim 1, wherein the amino acid sequence of the cytotoxic peptide is selected from the group consisting of: i) QLGKKKHRRRPSKKKRHW (SEQ ID NO: 3), ii) QLGRRRHRRRPSRRRRHW (SEQ ID NO: 4), iii) QLGKKILAARPSKKKRHW (SEQ ID NO: 5), and iv) QLGAAAHRRRPSKKKRHW (SEQ ID NO: 38).

### Claim 4

A peptide conjugate comprising a cytotoxic peptide and a nanoparticle or a microparticle, wherein the cytotoxic peptide is conjugated to the nanoparticle or microparticle, and wherein the cytotoxic peptide is represented by the consensus sequence Q1-L2-G3-X4-X5-X6-X7-X8-X9-R10-P11-S12-X13-X14-X15-R16-H17-W18 (SEQ ID NO: 36),
wherein,
i) each of X4, X5, and X6 is any amino acid;
ii) X7 is histidine or leucine;
iii) X8 and X9 are independently K or R or H or A; and
iv) X13, X14 and X15 are independently K or R or H.

### Claim 5 (depends on 4)

The peptide conjugate of claim 4, wherein
v) X8 and X9 are the same, and are K or R or H or A; and
vi) X13, X14 and X15 are the same, and are K or R or H.

### Claim 6 (depends on 4)

The peptide conjugate of claim 4, wherein the amino acid sequence of the cytotoxic peptide is selected from the group consisting of: i) QLGKKKHRRRPSKKKRHW (SEQ ID NO: 3), ii) QLGRRRHRRRPSRRRRHW (SEQ ID NO: 4), iii) QLGKKILAARPSKKKRHW (SEQ ID NO: 5), and iv) QLGAAAHRRRPSKKKRHW (SEQ ID NO: 38).

### Claim 7 (depends on 4)

The peptide conjugate of claim 4, wherein the nanoparticle or microparticle is made from a material selected from the group consisting of metal, silica, carbon, polymeric materials, and mixtures thereof.

### Claim 8 (depends on 1)

The recombinant peptide of claim 1, wherein the peptide has a modification selected from the group consisting of glycosylation, sulfation, phosphorylation, ubiquitination, methylation, lipidation, biotinylation, hydroxylation and acetylation.

### Claim 9 (depends on 1)

The recombinant peptide of claim 1, comprising the peptide of SEQ ID NO: 15.