Peptidomimetic macrocycles

Patent metadata

Field	Value
Publication number	US-8927500-B2
Application number	US-201313767852-A
Country	US
Kind code	B2
Filing date	Feb 14, 2013
Priority date	Feb 15, 2012
Publication date	Jan 6, 2015
Grant date	Jan 6, 2015

Abstract

Provided herein are peptidomimetic macrocycles containing amino acid sequences with at least two modified amino acids that form an intramolecular cross-link that can help to stabilize a secondary structure of the amino acid sequence. Suitable sequences for stabilization include those with homology to the p53 protein. These sequences can bind to the MDM2 and/or MDMX proteins. Also provided herein are methods of using such macrocycles for the treatment of diseases and disorders, such as cancers or other disorders characterized by a low level or low activity of a p53 protein or high level of activity of a MDM2 and/or MDMX protein.

First claim

What is claimed is:

1. A peptidomimetic macrocycle of Formula:

or a pharmaceutically-acceptable salt thereof
wherein:
each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaa 9 , and Xaa 10 is independently an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaa 9 , and Xaa 10 are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3 -X 4 -Glu 5 -Tyr 6 -Trp 7 -Ala 8 -Gln 9 -Leu 10 /Cba 10 -X 11 -Ala 12 (SEQ ID NO: 9), where each of X 4 and X 11 is independently an amino acid;
each D is independently an amino acid;
each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);
R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids; each L and L′ is independently a macrocycle-forming linker of the formula -L 1 -L 2 -;
each L 1 and L 2 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 -K-R 4 -] n , each being optionally substituted with R 5 ;
each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ;
each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each K is independently O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ;

each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;
each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

R 7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue;
R 5 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue;
v is an integer from 1-1000;
w is an integer from 3-1000; and
n is an integer from 1-5.

2. A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c, wherein the peptidomimetic macrocycle has the formula:

or a pharmaceutically-acceptable salt thereof,
wherein:
each A, C, and D is independently an amino acid;
each B is independently an amino acid,

[—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);
each R 1 and R 2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;
each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ;
each L and L′ is independently a macrocycle-forming linker of the formula -L 1 -L 2 -;
each L 1 and L 2 and L 3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 -K-R 4 —] n , each being optionally substituted with R 5 ;
each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each K is independently O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ;

each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;
each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R 7 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue;
each R 8 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue;
each v is independently an integer from 1-1000;
each w is independently an integer from 3-1000;
u is an integer from 1-10;
each x, y and z is independently an integer from 0-10; and
each n is independently an integer from 1-5.

3. A peptidomimetic macrocycle of Formula:

or pharmaceutically-acceptable salt thereof
wherein:
each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaa 9 , and Xa 10 is independently an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaa 9 , and Xaa 10 are the same amino acids as the amino acid at the corresponding position of the sequence Phe 3 -X 4 -His 5 -Tyr 6 -Trp 7 -Ala 8 -Gln 9 -Leu 10 -X 11 -Ser 12 (SEQ ID NO: 8) or Phe 3 -X 4 -Glu 5 -Tyr 6 -Trp 7 -Ala 8 -Gln 9 -Leu 10 /Cba 10 -X 11 -Ala 12 (SEQ ID NO: 9), wherein each X 4 and X 11 is independently an amino acid;
each D is independently an amino acid;
each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);
R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;
each L or L′ is independently a macrocycle-forming linker;
each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SO 2 R 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;
each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

R 7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue;
R 8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue;
v is an integer from 1-1000; and
w is an integer from 3-1000.

4. The peptidomimetic macrocycle or pharmaceutically-acceptable

Assignees

• Aileron Therapeutics Inc

Inventors

• Guerlavais Vincent
• Elkin Carl
• Nash Huw M
• Sawyer Tomi K
• Graves Bradford J
• Feyfant Eric

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K38/17

  from animals; from humans {(enzyme inhibitors A61K38/005)} · CPC title

• A61K38/10 Primary

  Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• C07K14/4746 Primary

  p53 · CPC title