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-10213477-B2
Publication Date
2019-02-26
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 relates to treating cancer by administering a therapeutically effective amount of a pharmaceutical product that includes a first therapeutic agent and a second therapeutic agent. The first therapeutic agent is an inhibitor of an interaction between p53 and MDM2 and/or an inhibitor of an interaction between p53 and MDMX, and is a peptidomimetic macrocycle comprising an amino acid sequence with at least about 90% sequence identity to an amino acid sequence selected from SEQ ID NOs: 10-457, or a pharmaceutically acceptable salt thereof.
The peptidomimetic macrocycle has a formula defined by independently variable amino acid positions, including Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10, with at least three of these positions corresponding to the amino acids of Phe3-X4-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12 (SEQ ID NO: 8) or Phe3-X4-Glu5-Tyr6-Trp7-Ala8-Gln9-Leu10/Cba10-X11-Ala12 (SEQ ID NO: 9). The formula further includes D residues and E residues, macrocycle-forming linkers L and L′, and substituent options that include fluorescent moieties, radioisotopes, and therapeutic-agent options.
The disclosure also describes cyclic β-amino acid analogs, non-essential amino acid residue, essential amino acid residue, conservative amino acid substitution, terminal capping groups, and macrocycle-forming linker terminology used to build macrocyclic structures. The document includes structural determination of peptidomimetic macrocycles bound to zebrafish MDMX by x-ray co-crystallography, fluorescence-polarization binding/competition assays, and cell-based assays for cell viability, p21 ELISA, caspase-3/7 detection, and an image-based 53BP1/Grip-style redistribution assay.
Claims Coverage
The consolidated claim coverage identifies one independent cancer-treatment claim. It combines a peptidomimetic macrocycle inhibitor of p53-MDM2 and/or p53-MDMX interactions with a chemotherapeutic agent, and includes high sequence identity and defined Formula constraints for the macrocycle.
Combination treatment with p53-mdm2/mdmx inhibitor macrocycle and chemotherapeutic agent
A method for treating a cancer by administering to a subject a therapeutically effective amount of a pharmaceutical product comprising a first therapeutic agent that is an inhibitor of an interaction between p53 and MDM2 and/or an inhibitor of an interaction between p53 and MDMX, and a second therapeutic agent comprising a chemotherapeutic agent.
Peptidomimetic macrocycle with high sequence identity
The first therapeutic agent is a peptidomimetic macrocycle comprising an amino acid sequence with at least about 90% sequence identity to an amino acid sequence selected from SEQ ID NOs: 10-457, or a pharmaceutically acceptable salt thereof.
Defined macrocycle formula with constrained residues and linkers
The peptidomimetic macrocycle has a formula in which Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 are independently amino acids, with at least three of these positions matching the corresponding amino acids of SEQ ID NO: 8 or SEQ ID NO: 9, and with D residues, E residues, macrocycle-forming linkers L and L′, and variable substituents defined as specified.
The independent claim coverage is directed to administering a therapeutically effective combination of a peptidomimetic macrocycle inhibitor of p53-MDM2 and/or p53-MDMX interactions and a chemotherapeutic agent, with the macrocycle constrained by sequence identity and formula-based residue and linker definitions.
Stated Advantages
The resulting Formula (I) can be obtained in equal or higher amounts than the corresponding Z isomer.
Improved biological activity over uncrosslinked counterparts.
Improved binding affinity/MDMX versus MDM2 selectivity.
Increased apoptosis/anti-tumor efficacy in p53+ versus p53− contexts.
Improved solubility/cell permeability relative to control macrocycles.
Documented Applications
Treating a subject with cancer by administering a therapeutically effective amount of a pharmaceutical product comprising the described peptidomimetic macrocycle inhibitor and a chemotherapeutic agent.
The treated cancer is selected from head and neck cancer, melanoma, lung cancer, breast cancer, glioma, or a hematological cancer.
Therapeutic use for p53/MDM2/MDMX dysregulation.
Characterization and binding/functional assay performance for peptidomimetic macrocycles directed to MDMX/MDM2 and p53 pathway targets, including crystallography, circular dichroism (CD), fluorescence polarization (FP), ELISA competition binding assay, and cell viability assays, with summarized outcomes in performance tables.
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