Peptidomimetic macrocycles
Inventors
Guerlavais, Vincent • Elkin, Carl • Nash, Huw M. • Sawyer, Tomi K. • Graves, Bradford J. • Feyfant, Eric
Assignees
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Publication Number
US-9505804-B2
Publication Date
2016-11-29
Expiration Date
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.
Core Innovation
The invention concerns peptidomimetic macrocycles comprising an amino acid sequence at least about 90% identical to an amino acid sequence selected from SEQ ID NOs: 10-457. The macrocycles are defined by a formula in which A, C, D, and E are amino acids and B is independently an amino acid, with macrocycle-forming linkers L and L′ and variable substituent and linker components.
The document describes peptidomimetic macrocycles that can exist as multiple isomers arising from the E/Z configuration of an olefin crosslinker. It states that an E crosslinker isomer and a Z crosslinker isomer are distinguishable isomers associated with the macrocycle structure, and that one isomer may have improved properties relative to the other isomer.
The invention further relates to p53-derived peptidomimetic macrocycles stabilized by an intramolecular cross-link, wherein the macrocycle binds MDM2 and/or MDMX to restore p53 activity. The document also describes a catalyst-based approach for preparing peptidomimetic macrocycles of Formula (Ia) from a corresponding precursor of Formula (II), including selectivity favoring formation of an Ia over a Z isomer.
Claims Coverage
The consolidated claim coverage includes two independent claims: one to a peptidomimetic macrocycle composition and one to a method of preparing a composition. Across the claims, the scope centers on highly conserved amino acid sequence identity to specified SEQ ID NOs, a detailed macrocycle formula with variable linker and substituent groups, a hydrophobic C-terminal amino acid represented by E, and catalyst-treated conversion to Formula (Ia).
Highly conserved peptidomimetic macrocycle amino acid sequence identity
A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-457, or in the method claim 95% to 100% identical to an amino acid sequence selected from SEQ ID NOs: 10-457.
Peptidomimetic macrocycle formula defined by variable linker and substituent groups
The peptidomimetic macrocycle has a formula defining amino-acid components A, C, D, and E; B components; macrocycle-forming linkers L and L′ of the formula -L1-L2-; and variable substituent and linker parameters including R1, R2, R3, L3, K, R5, R6, R7, R8, v, w, u, x, y, z, and n.
Hydrophobic C-terminal E side chain
A first C-terminal amino acid represented by E comprises a hydrophobic side chain, including the conditional statement when w>1 a first or second C-terminal amino acid represented by E comprises a hydrophobic side chain.
Exclusion of specified sequences
The peptidomimetic macrocycle or pharmaceutically acceptable salt thereof is not any of specified SEQ ID NOs, including SEQ ID NOs: 728, 729, 737-740, 826, 828, 839-841, 857, 860, 864, 866, 868, 872, 881, 884, 897, 911, 914, 915, 920, 921, 923, 926-942, 960-973, 975-977, 1013-1016, 1069, 1070, 1076, 1088, 1089, 1095-1124, 1127-1132, 1136-1139, 1142, 1144, 1149-1151, 1172, 1173, 1178-1201, 1206-1210, 1214-1216, 1246-1252, 1256-1266, 1270, 1272-1278, 1284, 1288, 1289, 1295-1297, 1327, 1336-1339, 1344, 1345, 1360, 1362, 1363, 1369, 1378-1380, 1391, 1392, 1419-1421, 1430, 1431, 1434, 1436, 1438, 1451, 1453, 1473, 1478, or 1502.
Catalyst-treated conversion to a macrocycle composition of Formula (Ia)
A method of preparing a composition comprising a peptidomimetic macrocycle of Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein the method comprises treating a compound of Formula (II) or a pharmaceutically acceptable salt thereof with a catalyst to result in the compound of Formula (Ia) or pharmaceutically acceptable salt thereof.
E-double bond representation
In the compound of Formula (Ia) or pharmaceutically acceptable salt thereof and in the compound of Formula (II) or pharmaceutically acceptable salt thereof, (E) represents a trans double bond or an E-double bond.
The claim scope is directed to peptidomimetic macrocycles with conserved amino-acid sequence identity to SEQ ID NOs: 10-457 and a structured macrocycle formula with variable linker and substituent parameters. A separate independent claim covers catalyst treatment of a Formula (II) compound to generate a Formula (Ia) macrocycle composition, with the stated hydrophobic C-terminal E side chain and specified exclusions.
Stated Advantages
Improved solubility.
Improved target affinity.
Improved in vivo efficacy.
Improved in vitro efficacy.
Improved helicity.
Improved cell permeability.
Improved binding affinity.
Apoptosis induction.
In vitro and in vivo anti-tumor efficacy.
Documented Applications
Treating p53-low cancers and cancers with MDM2/MDMX-high activity by restoring p53 activity through binding of MDM2 and/or MDMX using the peptidomimetic macrocycles.
Modulating p53 activity by antagonizing interactions between p53 and MDM2 proteins and/or between p53 and MDMX proteins in a subject via administering a therapeutically-effective amount of a peptidomimetic macrocycle or pharmaceutically acceptable salt thereof.
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