Peptidomimetic macrocycles
Inventors
Guerlavais, Vincent • Elkin, Carl • Nash, Huw M. • Sawyer, Tomi K. • Graves, Bradford J. • Feyfant, Eric
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10967042-B2
Publication Date
2021-04-06
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 peptidomimetic macrocycles and pharmaceutical compositions in a unit dosage form that include 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 interaction between p53 and MDMX, and the first therapeutic agent is a peptidomimetic macrocycle of a Formula.
The macrocycle is defined by variable amino acid positions Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10, each independently an amino acid, with at least three of those positions corresponding to the amino acids at corresponding positions of SEQ ID NO: 8 or SEQ ID NO: 9. The structure further specifies D and E amino acids, with each D independently an amino acid and each E independently selected from Ala, D-Ala, Aib, Sar, and Ser.
The Formula further specifies side-chain and linker substituents including R1, R2, R6, R7, and R8, macrocycle-forming linkers L and L′, and integer parameters v from 1 to 10 and w from 3 to 10. The macrocycles are described as peptide-like but constrained into a macrocyclic architecture to present a p53 alpha-helical secondary structure for interaction with MDM2 and/or MDMX, and some E versus Z crosslinker olefin isomers may differ in solubility, target affinity, efficacy, helicity, or cell permeability.
Claims Coverage
The independent claims center on a unit dosage pharmaceutical composition containing a peptidomimetic macrocycle inhibitor of p53-MDM2 and/or p53-MDMX interactions together with a chemotherapeutic agent. The coverage focuses on the macrocycle Formula, the SEQ ID NO: 8 or SEQ ID NO: 9 positional correspondence, the D and E residue definitions, the macrocycle-forming linkers and side-chain substituent options, and the integer parameters v and w.
Pharmaceutical composition with p53 interaction inhibitor plus chemotherapeutic agent
A pharmaceutical composition in a unit dosage form comprising a first therapeutic agent that is an inhibitor of an interaction between p53 and MDM2 and/or an interaction between p53 and MDMX, and a second therapeutic agent that is a chemotherapeutic agent, wherein the first therapeutic agent is a peptidomimetic macrocycle of a Formula.
Peptidomimetic macrocycle scaffold defined by variable amino-acid-like positions and reference sequences
Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 are independently amino acids, with at least three of those positions matching the amino acid at corresponding positions of SEQ ID NO: 8 or SEQ ID NO: 9.
D and E amino-acid selection with macrocycle-forming linker definitions
Each D is independently an amino acid and each E is independently selected from Ala, D-Ala, Aib, Sar, and Ser, with R1 and R2 optionally forming a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids, and L and L′ being macrocycle-forming linkers.
Substituent variability and integer indices v and w
The macrocycle is further defined with substituent options for R1, R2, R6, R7, and R8, and with v being an integer from 1 to 10 and w being an integer from 3 to 10.
Overall, the claim coverage centers on a unit dosage pharmaceutical composition combining a chemotherapeutic agent with a peptidomimetic macrocycle inhibitor of p53-MDM2 and/or p53-MDMX interactions, where the macrocycle is defined by variable amino-acid positions tied to reference sequences, includes D and E amino-acid selections, uses macrocycle-forming linkers, and specifies substituent variability together with the integer indices v and w.
Stated Advantages
One isomer may have improved solubility relative to the other.
One isomer may have improved target affinity relative to the other.
One isomer may have improved efficacy relative to the other.
One isomer may have improved helicity relative to the other.
One isomer may have improved cell permeability relative to the other.
Restores or activates p53 by modulating MDM2 and/or MDMX via stabilized p53 alpha-helical binding.
Enhanced binding affinity and anti-tumor activity in p53-positive settings, including improved apoptosis induction.
Improved solubility, permeability, and cellular efficacy.
Documented Applications
Used as a unit dosage pharmaceutical composition that includes a first therapeutic agent inhibiting p53-MDM2 and/or p53-MDMX interactions together with a chemotherapeutic agent.
Therapeutic treatment of cancers, including head and neck, melanoma, lung, breast, and glioma, by using the described pharmaceutical composition to restore or activate p53.
Therapeutic use for p53 pathway disorders by restoring or activating p53 through MDM2 and/or MDMX interaction modulation.
Interested in licensing this patent?