Stabilized P53 peptides and uses thereof
Inventors
Bernal, Federico • Walensky, Loren D. • Verdine, Gregory L. • Korsmeyer, Stanley J.
Assignees
Dana Farber Cancer Institute Inc • Harvard University • Rein Therapeutics Inc
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Publication Number
US-10202431-B2
Publication Date
2019-02-12
Expiration Date
Abstract
Cross-linked peptides related to human p53 and bind to HMD2 or a family member of HDM2 useful for promoting apoptosis, e.g., in the treatment of and identifying therapeutic agents that binding to HMD2 or a family member of HDM2.
Core Innovation
Stably internally cross-linked, alpha-helical p53 stapled peptides (SAH-p53) are disclosed that are designed to inhibit HDM2/HDMX binding and thereby restore p53 activity. The disclosed peptides include a span of 8 contiguous amino acid residues derived from human p53 in which side chains at selected positions are replaced by a tether/cross-linking group. The peptide structure is defined using Formulas (I) and (II) with extensive substituent and stereochemical options, and the span comprises Phe, Leu, and Trp.
The document describes peptide binding to HDM2 with a stated affinity range and associates HDM2 binding with p53 reactivation outcomes. The described biological rationale includes restoring p53 activity in disorders with reduced p53 activity, including cancers with wild-type p53 rendered vulnerable by HDM2 targeting. Representative SAH-p53 sequences and optional inactive controls (such as F19A) are described in the narrative.
The disclosed SAH-p53 peptides are further associated with enhanced alpha-helicity and improved biological behavior, including serum protease stability and cell permeability for second-generation designs. The narrative provides figure-based findings including enhanced alpha-helicity, subnanomolar HDM2 binding for SAH-p53, p53 protein accumulation and p21 induction, and apoptosis induction in HDM2-overexpressing cells, together with uptake/interaction evidence using fluorescence assays and co-immunoprecipitation.
Claims Coverage
The provided material includes two independent claims covering the SAH-p53 peptide of Formula (I): one directed to treating reduced p53 activity by administering the peptide, and one directed to preparing the same peptide by solid phase peptide chemistry followed by ring-closing metathesis. Together, the claims emphasize the structurally defined 8-residue p53-derived span, HDM2 binding, and the metathesis-based production route.
Treating reduced p53 activity with a specific HDM2-binding Formula (I) peptide
Administering to a subject having a disorder with reduced p53 activity a therapeutically effective amount of a peptide of Formula (I) or pharmaceutically acceptable salt, where the peptide comprises a span of 8 contiguous amino acid residues that includes Phe, Leu, and Trp, and where the peptide exhibits a binding affinity for HDM2 from about 0.75 nM to about 110 nM.
Producing Formula (I) peptide by solid phase synthesis and ring-closing metathesis
Preparing a peptide of Formula (I) or a pharmaceutically acceptable salt by synthesizing the peptide using solid phase peptide chemistry, where the synthesized peptide comprises at least two moieties capable of undergoing a metathesis reaction, and performing a ring-closing metathesis reaction to produce the peptide.
The claim coverage is centered on SAH-p53 peptides of Formula (I) featuring an 8-residue p53-derived span with Phe, Leu, and Trp and an HDM2 binding affinity between about 0.75 nM and about 110 nM, with one independent claim directed to treatment of reduced p53 activity and the other to preparation by solid phase peptide chemistry plus ring-closing metathesis.
Stated Advantages
Restores p53 activity by inhibiting HDM2/HDMX binding.
Enhanced alpha-helicity.
Improved protease stability.
Serum half-life stated as about 4×.
Induces p53 protein accumulation and p21 induction.
Induces apoptosis in HDM2-overexpressing cells.
Displays cell permeability for second-generation designs.
Documented Applications
Treating disorders with reduced p53 activity by administering the disclosed SAH-p53 stapled peptides.
Treating cancers with wild-type p53 that are vulnerable by HDM2 targeting.
Therapeutic administration of the peptides to achieve p53 reactivation outcomes including p53 protein accumulation, p21 induction, and apoptosis induction.
HDM2 binding evaluation and assays for alpha-helicity, protease stability or serum half-life, and uptake or interaction evidence using fluorescence assays and co-immunoprecipitation.
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