PARP inhibitor compounds, compositions and methods of use
Inventors
Xu, Weizheng • Delahanty, Greg • Wei, Ling • Zhang, Jie
Assignees
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Publication Number
US-8894989-B2
Publication Date
2014-11-25
Expiration Date
Abstract
The present invention relates to tetraaza phenalen-3-one compounds which inhibit poly(ADP-ribose) polymerase (PARP) and are useful in the chemosensitization of cancer therapeutics. The induction of peripheral neuropathy is a common side-effect of many of the conventional and newer chemotherapies. The present invention further provides means to reliably prevent or cure chemotherapy-induced neuropathy. The invention also relates to the use of the disclosed PARP inhibitor compounds in enhancing the efficacy of chemotherapeutic agents such as temozolomide. The invention also relates to the use of the disclosed PARP inhibitor compounds to radiosensitize tumor cells to ionizing radiation. The invention also relates to the use of the disclosed PARP inhibitor compounds for treatment of cancers with DNA repair defects.
Core Innovation
The invention relates to PARP inhibitor compounds of Formula (I), including compound 37 and compound 13, and pharmaceutically acceptable salts or esters thereof. The compounds are intended for medical use in cancer therapy, including chemosensitizing cancer cells in a mammal in need of chemotherapy, and are also described in pharmaceutical compositions comprising a Formula (I) compound and pharmaceutically acceptable carriers.
The disclosure addresses cancer associated with homologous recombination defects, including BRCA1 defects, BRCA2 defects, and Fanconi anemia-associated cancers, and links the approach to potentiation of cytotoxic effects of chemotherapeutic agents and ionizing radiation. It further frames the compounds as capable of chemosensitizing and radiosensitizing tumor cells, and identifies chemotherapy-induced peripheral neuropathy as a limiting side effect with prevention or mitigation through timing relative to chemotherapy.
The document includes biological evaluation of the compounds by PARP inhibitory activity testing, with reported IC50 values and a recombinant human PARP enzyme assay. It also describes in vivo efficacy and pharmacokinetic rationale, including higher brain-to-plasma ratios than a related prior-art compound, and supports CNS penetration and therapeutic benefit.
Claims Coverage
The claim coverage centers on a method for chemosensitizing cancer cells in a mammal in need of chemotherapy by administering compound 37 or pharmaceutically acceptable salts or esters thereof. The inventive features also refine the compound by the provided chemical structure images, limit the target to an enumerated group of cancer cell types, restrict the subject to a human mammal, and optionally combine administration with a selected chemotherapeutic agent.
Administering compound 37 for chemosensitizing cancer cells
A method for chemosensitizing cancer cells in a mammal in need of chemotherapy by administering a compound selected from compound 37 and pharmaceutically acceptable salts or esters thereof.
Using pharmaceutically acceptable salts or esters of compound 37
Administering the compound as a pharmaceutically acceptable salt or ester of compound 37.
Defining the compound by provided chemical structure images
Performing the method using a compound specified by the provided chemical structure images.
Targeting an enumerated group of cancer cell types
Selecting the cancer cells from a specified group of named cancer types.
Applying the method to a human mammal
Applying the chemosensitizing method to a human mammal in need of chemotherapy.
Combining with a selected chemotherapeutic agent
Further administering a selected chemotherapeutic agent chosen from a specified group or mixtures thereof.
Overall, the claim coverage is directed to chemosensitizing cancer cells by administering compound 37, including pharmaceutically acceptable salts or esters, with dependent refinements for the compound form, the cancer-cell target set, treatment of a human mammal, and optional combination with a listed chemotherapeutic agent.
Stated Advantages
Significantly increases survival versus TMZ alone in intracranial B16 melanoma and SJGBM2 glioma mouse models.
Provides combination benefit with TMZ, including in a glioma context where TMZ is ineffective alone.
Enhances radiation treatment, producing significant tumor growth inhibition in a head and neck squamous cell carcinoma model.
In BRCA-1-deficient tumors, retards tumor growth and delays onset to endpoint compared with vehicle and compared with a PARP inhibitor control.
Provides pharmacokinetic rationale via higher brain-to-plasma ratios for disclosed Formula (I) compounds compared with a related prior-art compound.
Supports CNS penetration and therapeutic benefit based on the unexpectedly higher brain-to-plasma ratios.
Potentiates cytotoxic effects of DNA-damaging chemotherapeutic agents.
Treats chemotherapy-induced peripheral neuropathy.
Documented Applications
In vivo efficacy testing of chemosensitizing compounds using oral dosing of compound 13 in combination with temozolomide (TMZ) in intracranial B16 melanoma and SJGBM2 glioma mouse models.
In vivo efficacy assessment of compound 37 versus TMZ, including intracranial glioma where TMZ is ineffective alone, and reporting combination benefit with TMZ.
Enhancing radiation treatment in a head and neck squamous cell carcinoma model (JHU012) by administering compound 37, with significant tumor growth inhibition reported.
Efficacy assessment in BRCA-1-deficient tumors, where compound 37 retards tumor growth and delays onset to endpoint versus vehicle and versus a PARP inhibitor control.
Chemosensitizing and radiosensitizing tumors, including potentiating cytotoxic effects of DNA-damaging chemotherapeutic agents.
Treating cancers associated with homologous recombination (HR) pathway defects, including BRCA1/BRCA2 defects and Fanconi anemia.
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