Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
Inventors
Guerlavais, Vincent • Conlee, Christopher R. • Lentini, Scott Paul
Assignees
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Publication Number
US-8987414-B2
Publication Date
2015-03-24
Expiration Date
Abstract
Provided herein are peptidomimetic macrocycles and methods of using such macrocycles for the treatment of disease.
Core Innovation
The invention relates to peptidomimetic macrocycles comprising an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO. 455. The macrocycles are defined by formulae with amino-acid positions A, B, C, D, and E, macrocycle-forming linkers L and L′, and variable integer parameters v, w, u, x, y, z, and n, together with substituent definitions for R1 through R8 and K. The scope includes isomers, pharmaceutically acceptable salts, and macrocycles with linker and residue constraints at the alpha position of D or E amino acids.
A central feature is the use of intramolecular cross-linked p53 mimics, including triazole-containing macrocycles, thioether/tethered crosslinks, and bis-sulfhydryl peptidomimetic macrocycles. Crosslinking is used to stabilize an α-helix and to improve biological performance by antagonizing p53–MDM2 and p53–MDMX interactions. The document also describes excluded macrocycle variants, including certain crosslink types and cysteine stereochemistry and crosslinker patterns.
The document further describes synthetic schemes for producing triazole-containing and bis-sulfhydryl peptidomimetic macrocycles through azido/alkynyl intermediates, macrocyclization, selective protection/deprotection, alkylation, and cyclization. It also describes representative macrocycle structures, sequence patterns, and performance characterization context including α-helicity, MDM2 and MDMX binding, cell viability, p21 ELISA, caspase 3 detection, p53-MDM2 redistribution, LDH release, and solubility determination. The macrocycles are associated with therapeutic applications in cancer and with improved binding affinity, apoptosis induction, anti-tumor efficacy, solubility, and cell permeability in the documented comparisons.
Claims Coverage
The consolidated claims coverage identifies one independent claim directed to a peptidomimetic macrocycle having at least 90% identity to SEQ ID NO. 455 and a detailed macrocycle formula with independently defined residues, linkers, substituents, and integer ranges. The provided dependent coverage refines the scaffold with comparative performance, parameter constraints, specific sequence segments, and therapeutic administration for cancer.
Peptidomimetic macrocycle with SEQ ID NO. 455 sequence identity
A peptidomimetic macrocycle, isomer, or pharmaceutically acceptable salt comprising an amino acid sequence at least 90% identical to SEQ ID NO. 455.
Macrocycle chemical formula with amino-acid positions A, B, C, D, and E
A macrocycle formula in which A, C, D, and E are independently amino acids and B is independently an amino acid, with macrocycle-forming linker features including L and L′ and linker placement at the alpha position of one of D or E.
Macrocycle-forming linkers L and L′ with variable linker units
L and L′ are independently macrocycle-forming linkers defined through L1, L2, and L3 units, with L1, L2, and L3 independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, or heterocycloarylene, optionally substituted with R5.
Integer parameter constraints for macrocycle structure
The macrocycle is defined by integer variables v, w, u, x, y, z, and n within specified ranges.
Comparative improvements in MDM2/MDMX binding affinity and solubility
Claims provide improved binding affinity to MDM2 or MDMX and improved solubility compared with corresponding macrocycles having w values of 0, 1, or 2.
Therapeutic administration for treating cancer
A method for treating cancer in a subject by administering a peptidomimetic macrocycle, an isomer of it, or a pharmaceutically acceptable salt.
Claim coverage centers on a peptidomimetic macrocycle scaffold constrained by sequence identity to SEQ ID NO. 455, macrocycle-forming linkers L and L′, residue and substituent definitions, and integer parameter ranges, with dependent refinements for performance and cancer treatment.
Stated Advantages
Stabilizes an α-helix and improves biological performance.
Improves binding affinity by antagonizing p53–MDM2 and p53–MDMX interactions.
Induces apoptosis.
Provides anti-tumor efficacy in p53-positive cells/tumors relative to p53-negative/mutant controls.
Improved solubility versus corresponding macrocycles with w of 0, 1, or 2.
Potential differences in solubility, affinity, efficacy, and cell permeability among olefin crosslinker E/Z isomers are described.
Documented Applications
Treating cancer in a subject by administering a peptidomimetic macrocycle, an isomer of it, or a pharmaceutically acceptable salt.
Modulating p53/MDM2/MDMX activity in the context of cancer treatment outcomes.
Cancer treatment via administration of macrocycles is identified as a documented use case.
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