Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
Inventors
Guerlavais, Vincent • Conlee, Christopher R. • Lentini, Scott Paul
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10227380-B2
Publication Date
2019-03-12
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 60% identical to SEQ ID NO. 448, or at least 80% identical to SEQ ID NO. 448, and to pharmaceutically acceptable salts thereof. The peptidomimetic macrocycle is defined by a specified macrocycle formula in which A, C, D, and E are independently amino acids and B is independently an amino acid.
The macrocycle framework includes substituents R1 and R2, independently selected from hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, optionally substituted with halo-. At least one of R1 and R2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids, and each L and L' is independently a macrocycle-forming linker with broadly defined linker subcomponents L1, L2, and L3.
The structure definition further specifies R3, R4, K, R5, and integer parameters v, w, u, x, y, z, and n. K is independently O, S, SO, SO2, CO, CO2, or CONR3, and R5 can be halogen, -OR6, -N(R6)2, -SR6, -SOR6, -SO2R6, -CO2R6, a fluorescent moiety, a radioisotope, or a therapeutic agent.
Claims Coverage
The consolidated claim coverage centers on one independent peptidomimetic macrocycle scaffold defined by sequence identity to SEQ ID NO. 448 and a specified macrocycle formula. The inventive features merge the repeated structural definitions across the inputs and include dependent refinements for tighter sequence identity, parameter constraints, improved binding, and cancer treatment use.
Peptidomimetic macrocycle with SEQ ID NO. 448 identity requirement
A peptidomimetic macrocycle comprising an amino acid sequence at least 60% identical to SEQ ID NO. 448, or at least 80% identical to SEQ ID NO. 448, and a pharmaceutically acceptable salt thereof.
Macrocycle formula with amino acid components A, B, C, D, and E
A peptidomimetic macrocycle having a formula wherein A, C, D, and E are independently amino acids and B is independently an amino acid.
R1 and R2 form a macrocycle-forming linker L'
Each R1 and R2 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, optionally substituted with halo-, and at least one of R1 and R2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids.
Macrocycle-forming linkers L and L' with variable linker components
Each L and L' is independently a macrocycle-forming linker with L1, L2, and L3 independently selected from alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or a substituted [-R4-K-R4-] motif, each optionally substituted with R5.
Substituent and attachment parameterization via R3, R4, K, and R5
R3 and R4 are independently selected from defined groups and hetero/hydrocarbon moieties; K is independently O, S, SO, SO2, CO, CO2, or CONR3; and R5 is independently halogen, -OR6, -N(R6)2, -SR6, -SOR6, -SO2R6, -CO2R6, a fluorescent moiety, a radioisotope, or a therapeutic agent, with R6 independently selected from H and corresponding group choices.
Macrocycle variant integer parameters
v and w are independently an integer from 1 to 1000, u is an integer from 1 to 10, x, y, and z are independently an integer from 0 to 10, and n is independently an integer from 1 to 5.
Improved binding relative to w = 0, 1, or 2 variants
A peptidomimetic macrocycle is described as having improved binding affinity to MDM2 or MDMX compared with a corresponding peptidomimetic macrocycle having w values of 0, 1, or 2.
Cancer treatment by administering the macrocycle
A method for treating cancer in a subject by administering a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage is directed to a peptidomimetic macrocycle scaffold defined by sequence identity to SEQ ID NO. 448 and a specified macrocycle formula using R1/R2-driven linker formation, broadly defined linker and substituent options, and integer variant parameters. The consolidated dependent refinements also include tighter sequence identity, improved binding to MDM2 or MDMX, and treatment of cancer by administration.
Stated Advantages
Improved binding affinity to MDM2 or MDMX compared with corresponding peptidomimetic macrocycles having w values of 0, 1, or 2.
Improved in vitro anti-tumor efficacy.
Improved in vivo anti-tumor efficacy.
Improved apoptosis induction.
Improved solubility.
Improved cell permeability.
Improved MDMX/MDM2 ratio.
Cellular uptake modifications, including lipidating and PEGylating.
Alpha-helix motifs stabilized by linker length parameters.
Documented Applications
Treating cancer in a subject by administering a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof.
Interested in licensing this patent?