Peptidomimetic macrocycles and uses thereof
Inventors
Chen, Hubert • Annis, David Allen • Chang, Yong • Aivado, Manuel • Olson, Karen • VIAU, Chris
Assignees
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Publication Number
US-10253067-B2
Publication Date
2019-04-09
Expiration Date
Abstract
Methods for treating liquid cancer, determined to lack a p53 deactivation mutation, in a subject are provided. Also provided are peptidomimetic macrocycles for use in treatment of a liquid cancer, determined to lack a p53 deactivation mutation, in a subject.
Core Innovation
The invention concerns administering a peptidomimetic macrocycle, or a pharmaceutically acceptable salt thereof, to treat a liquid tumor in a human subject. The macrocycle binds to a protein in a p53 pathway, the liquid tumor has no p53 deactivating mutation, and the human subject is refractory to another treatment of the liquid tumor. The disclosure frames this therapeutic administration in a biomarker-defined patient context.
The peptidomimetic macrocycles are represented by Formula (I) and related formulas, with variable amino-acid, linker, crosslinker, and substituent definitions. The description includes macrocycle sequence representations associated with sequences in Tables 3, 3a, 3b, and 3c, together with SEQ ID NO: 8 and SEQ ID NO: 9 and sequence identity thresholds.
The disclosure further links these structures to p53 pathway regulators MDM2 and/or MDMX, including disruption of an interaction between p53 and MDM2 proteins. It also describes biomarker-related factors, p53 status, and evaluation concepts including p53 pathway re-activation, reduced proliferation, increased p21, and apoptosis.
Claims Coverage
The claim coverage is directed to a method of treating a liquid tumor in a human subject by administering a peptidomimetic macrocycle or a pharmaceutically acceptable salt that binds to a protein in a p53 pathway, limited to liquid tumors lacking a p53 deactivating mutation and to subjects refractory to another treatment. The inventive features include p53-pathway binding, disruption of p53-MDM2 interaction, nucleic-acid sequencing-based determination of mutation status, sequence-identity and Formula (I) structural constraints, optional combination therapy, and dosage range language.
Treating a refractory liquid tumor lacking p53 deactivating mutation with a p53-pathway binding peptidomimetic macrocycle
Administering to a human subject a therapeutically effective amount of a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof, wherein the peptidomimetic macrocycle or the pharmaceutically acceptable salt binds to a protein in a p53 pathway, wherein the liquid tumor has no p53 deactivating mutation, and wherein the human subject is refractory to another treatment of the liquid tumor.
Disrupting p53 and MDM2 interaction
Using a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof to disrupt an interaction between p53 and MDM2 proteins.
Determining absence of p53 deactivation mutation by DNA sequencing
Determining that a liquid tumor lacks a p53 deactivating mutation by DNA sequencing of nucleic acid encoding the p53 protein.
Sequence-identity constrained peptidomimetic macrocycles
Using a peptidomimetic macrocycle or its pharmaceutically acceptable salt that contains an amino acid sequence at least about 60% identical to sequences in Table 3, Table 3a, Table 3b, or Table 3c, or sequences identified by SEQ ID NO: 8 and SEQ ID NO: 9, where the macrocycle is defined by Formula (I) with specified amino-acid and substituent/linker variable definitions.
Therapeutic dosage range for administration
Administering a therapeutically effective amount of about 0.5 to about 10 mg per kilogram of body weight.
Combination therapy with at least one additional therapeutic agent
Further administering to a human subject a therapeutically effective amount of at least one additional therapeutic agent.
Overall, the claim coverage centers on administering a p53-pathway-binding peptidomimetic macrocycle to treat a refractory liquid tumor lacking a p53 deactivating mutation. The claim refinements add p53-MDM2 interaction disruption, mutation-status determination by DNA sequencing, table- and SEQ ID NO-based sequence identity constraints within Formula (I), a dosage range, and combination administration.
Stated Advantages
Re-activation of the p53 pathway in liquid cancers lacking p53 deactivating mutations and/or expressing wild-type p53.
Achievement of clinical response endpoints including survival-time extension as described in connection with treatment response and monitoring.
Biomarker-based monitoring of p53 pathway activity using markers such as p53, MDM2, MDMX, p21, MIC-1, and caspase.
Improved solubility
Improved target affinity
Improved efficacy
Improved helicity
Improved permeability
Reduced proliferation
Increased p21
Increased apoptosis
Documented Applications
Treating a liquid tumor in a human subject with no p53 deactivating mutation in a subject refractory to another treatment.
Re-activating the p53 pathway in liquid cancers lacking p53 deactivating mutations and/or expressing wild-type p53 via binding to a protein in the p53 pathway, including interactions involving MDM2 and MDMX.
Monitoring treatment response using imaging modalities and biomarker measurement, including CT, MRI, DCE-MRI, PET, FDG-PET, FLT-PET, p53, MDM2, MDMX, p21, MIC-1, and caspase, and assessing endpoints including survival-time extension.
Phase 1 clinical study plan for peptide 1 in advanced liquid cancers expressing WT p53, including p53 status determination, dosing regimens DR-A and DR-B, dose escalation, and schedules of assessments and PK/PD sampling.
Supporting p53-mediated cytotoxicity and PD biomarker evaluations in vitro and a preclinical activity, safety, and toxicology overview.
Cell penetrability and cell killing/efficacy readouts.
In vivo stability and in vivo efficacy readouts.
CT, MRI, and PET imaging, including IWG criteria.
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