# US 7,745,574 B2 · Compounds that regulate apoptosis

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- Number: US 7,745,574 B2
- Document ID: US7745574B2
- Status: Granted
- Kind: B2
- Application number: 11/433,783
- Filed: 2006-05-11
- Published: 2007-03-08
- Granted: 2010-06-29
- Earliest claimed: 2005-05-12
- Assignees: The Burnham Institute
- Inventors: Arnold Satterthwait; Xiao-kun Zhang; Xiuwen Zhu; Siva Kolluri
- Web page: https://patentgrep.com/patent/US7745574B2

## CPC

- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- A61P 35/00: Antineoplastic agents
- C07K 14/4747: {Apoptosis related proteins}
- C07K 14/70567: {Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors}
- 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)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)
- 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)

## Abstract

Compounds that modulate the function of anti-apoptotic proteins such as Bcl-2 and related Bcl-2 family members are identified. These compounds have the ability to convert the activity of Bcl-2-family member proteins from anti-apoptotic to pro-apoptotic. Methods for inducing or preventing apoptosis are described, together with methods for identifying molecules that induce or prevent apoptosis through interaction with Bcl-2-family members. Methods for treatment of proliferative diseases and neurodegenerative diseases using the modulators of Bcl-2 and related family members are also disclosed.

## Claims

### Claim 1

A compound comprising:
a peptide consisting of the sequence of SEQ ID NO:60 or mutation or fragment thereof, wherein the peptide is pro-apoptotic; and
a cell-penetrating-peptide, wherein said compound induces apoptosis of mammalian cells expressing Bcl-2 or Bcl-2 related proteins.

### Claim 2 (depends on 1)

The compound of claim 1, wherein said cell-penetrating peptide comprises transportan 10.

### Claim 3 (depends on 1)

The compound of claim 1, wherein said cell-penetrating peptide consists of penetratin (SEQ ID NO: 65).

### Claim 4 (depends on 1)

The compound of claim 1, wherein the pro-apoptotic fragment consists of the amino acid sequence Phe Gly Asp Trp Ile Asp Ser Ile Leu (SEQ ID NO:16).

### Claim 5 (depends on 1)

The compound of claim 1, wherein the pro-apoptotic fragment consists of the amino acid sequence Phe Ser Arg Ser Leu His Ser Leu Leu (SEQ ID NO:9).

### Claim 6 (depends on 1)

The compound of claim 1, wherein the pro-apoptotic fragment consists of the amino acid sequence Phe Ala Cys Leu Ser Ala Leu Val Leu (amino acid residues 37-45 of SEQ ID NO:60).

### Claim 7 (depends on 1)

The compound of claim 1, wherein the pro-apoptotic fragment consists of the amino acid sequence Phe Tyr Leu Lys Leu Glu Asp Leu Val (SEQ ID NO:18).

### Claim 8 (depends on 1)

The compound of claim 1, wherein the mutation is an amino acid deletion.

### Claim 9 (depends on 1)

The compound of claim 1, wherein the mutation is an amino acid insertion.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the mutation is a conservative amino acid substitution.

### Claim 11 (depends on 1)

The compound of claim 1, wherein the mutation is an amino acid substitution with Alanine.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the mutation is an amino acid substitution with a non-naturally occurring amino acid.

### Claim 13 (depends on 1)

The compound of claim 1, wherein the compound comprises one or more D-amino acids.