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-8927500-B2
Publication Date
2015-01-06
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, or pharmaceutically-acceptable salts thereof, defined by formula-based structures having specified amino-acid positions and residue classes. The macrocycle is defined with Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 as independently an amino acid, where at least three of these positions match the amino acid identities at corresponding positions of reference sequences SEQ ID NO: 8 or SEQ ID NO: 9. The macrocycle further includes D residues and E residues selected from Ala, D-Ala, Aib, Sar, and Ser, together with variable residue positions and substituent options.
The macrocycle scaffold is constrained by macrocycle-forming linkers L and L’ of defined formula forms (-L1-L2-) and by linker components and integer parameters including v, w, u, x, y, z, and n, with additional residue classes and substituent groups defined by allowable chemical classes. Sequence definitions include sequence-identity options of at least about 60% identity to sequences in Table 1, Table 1a, Table 1b, and Table 1c, and related embodiments specify positions such as A, B, C, D, E, R1, R2, R3, R4, R5, R6, R7, and R8 within the macrocycle formula.
The invention also relates to p53-derived peptidomimetic macrocycles comprising intramolecular cross-links that stabilize an alpha-helical secondary structure. The macrocycles target MDM2 and/or MDMX to liberate and restore functional p53, and a preparation method is described in which a compound of Formula (II) is treated with a catalyst to obtain Formula (Ia), with the outcome described as producing higher amounts of the corresponding Ia compound versus the corresponding Z isomer.
Claims Coverage
The consolidated independent claims cover composition and method claims for peptidomimetic macrocycles defined by formula variables, residue classes, linker definitions, and sequence-identity or position-matching rules. Across the independent claims, the inventive features center on the defined macrocycle scaffold, the reference-sequence constraints to SEQ ID NO: 8 and/or SEQ ID NO: 9 or Table 1/1a/1b/1c, and catalyst-mediated preparation of Formula (Ia) from Formula (II).
Peptidomimetic macrocycle with defined amino-acid substitutions and macrocycle-forming linker L/L’
A peptidomimetic macrocycle or pharmaceutically-acceptable salt defined by formula variables including Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 as independently an amino acid, with at least three positions matching corresponding residues of SEQ ID NO: 8 or SEQ ID NO: 9; D and E residues selected as defined; and macrocycle-forming linkers L and L’ of the form -L1-L2- with integer parameters v, w, and n.
Sequence-identity peptidomimetic macrocycle defined relative to Table 1/1a/1b/1c
A peptidomimetic macrocycle or pharmaceutically-acceptable salt comprising an amino acid sequence at least about 60% identical to an amino acid sequence in Table 1, Table 1a, Table 1b, and Table 1c, with a macrocycle formula defined by amino acids A, B, C, D, and E, linker definitions L and L’, substituent classes including R1 through R8, and integer parameters v, w, u, x, y, z, and n.
Catalyst-treated preparation for Formula (Ia) peptidomimetic macrocycle from Formula (II)
A method of preparing a composition comprising a peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of Formula (Ia) by treating Formula (II) with a catalyst to obtain Formula (Ia), where the macrocycle satisfies the sequence identity and structural constraints defined in the claims and the catalyst includes a ruthenium catalyst in one embodiment.
The independent claims collectively define peptidomimetic macrocycles by formula, residue, linker, and sequence constraints, and further define catalyst-mediated preparation of Formula (Ia) from Formula (II). The inventive scope is anchored in the macrocycle scaffold and its specified position-matching or sequence-identity relationships.
Stated Advantages
Improved in vivo induction of apoptosis in a p53-positive tumor compared to a corresponding peptidomimetic macrocycle.
Improved binding affinity to MDM2 or MDMX compared to a corresponding peptidomimetic macrocycle.
Reduced binding-affinity ratio of MDMX versus MDM2 compared with a corresponding peptidomimetic macrocycle.
Improved solubility relative to the other E/Z isomer.
Improved target affinity relative to the other E/Z isomer.
Improved in vivo/in vitro efficacy relative to the other E/Z isomer.
Improved helicity relative to the other E/Z isomer.
Improved cell permeability relative to the other E/Z isomer.
Improved binding affinity/selectivity versus variants with w=0–2 against the targeted MDM2 and/or MDMX.
Improved in vivo induction of apoptosis in a p53-positive tumor compared to a corresponding peptidomimetic macrocycle with w=0–2.
Improved in vitro and in vivo anti-tumor efficacy compared to corresponding variants with w=0–2.
Improved cell permeability/solubility compared to corresponding variants with w=0–2.
Produces higher amounts of the corresponding Ia compound versus the corresponding Z isomer.
Documented Applications
Induction of apoptosis in a p53-positive tumor (in vivo).
Binding to MDM2 and MDMX.
Zebrafish MDMX binding/co-crystallography characterization.
Fluorescence polarization binding/competition assays using an FAM labeled peptide.
Cellular assays with caspase and p21 readouts.
Xenograft study summaries.
Treating cancers and other p53/MDM2/MDMX pathway disorders using the p53-derived peptidomimetic macrocycles.
Use of fluorescence moieties, radioisotopes, and therapeutic agents as substituents within the described macrocycles.
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