Phosphoramidate alkylator prodrugs
Inventors
Matteucci, Mark • Duan, Jian-Xin • Jiao, Hailong
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9226932-B2
Publication Date
2016-01-05
Expiration Date
Abstract
Phosphoramidate alkylator prodrugs can be used to treat cancer when administered alone or in combination with one or more anti-neoplastic agents.
Core Innovation
The invention relates to hypoxia-activated phosphoramidate alkylator prodrugs for cancer and other hyperproliferative diseases. A Trigger is linked through a defined linker to a phosphoramidate alkylator prodrug structure, and the disclosure defines broad formulas with variable substituents, including bioreductive Trigger options, intercalator-capable moieties, and side-chain definitions.
The bioreductive groups include 1-N-alkyl-2-nitroimidazol-5-yl, 1-N-methyl-2-nitroimidazol-5-yl, 2-nitrofuran, nitroimidazole, nitrofuran, nitrothiophene, indole quinone, indole hydroquinone-like groups, and glucose or analog bioreductive group Z3. The disclosure also includes explicit exclusion and proviso rules, including restrictions on certain morpholine-ring combinations and exclusion of certain known glucose conjugates.
Upon activation under hypoxia, the phosphoramidate alkylator is released to form aziridine or aziridinium electrophiles, or active phosphoramidate alkylators described as free amino or modified phosphoramidate alkylators. The resulting hypoxic reduction scheme produces DNA alkylation and hypoxic cytotoxicity for treatment of cancer, including therapy-resistant and metastatic cancer contexts.
Claims Coverage
One independent claim is identified, directed to a method for treating cancer by administering TH302. Dependent refinements specify colorectal cancer, combination co-therapies with paclitaxel or gemcitabine, and daily weight-based dosing ranges with single or divided doses.
Administering TH302 to treat cancer
A method for treating cancer comprising administering to a patient in need of treatment for cancer a therapeutically effective dose of N,N′-bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester, TH302.
Daily weight-based TH302 dosing
Administering TH302 at a daily dose of 0.001 to 0.1 g per kg body weight in single or divided doses, or 0.1 to 35 mg/kg/day in single or divided doses.
Treating colorectal cancer
Applying the method where the cancer is colorectal cancer.
Combination with paclitaxel
Further administering a therapeutically effective dose of paclitaxel to the patient.
Combination with gemcitabine
Further administering a therapeutically effective dose of gemcitabine to the patient.
The claim coverage is anchored by therapeutic administration of TH302 for cancer treatment, with refinements for colorectal cancer, co-therapy with paclitaxel or gemcitabine, and specific daily or mg/kg/day dosing ranges in single or divided doses.
Stated Advantages
Reduced toxicity versus known agents such as ifosfamide and cyclophosphamide.
Altered toxic byproduct profiles, including reduced or absent acrolein and other toxic byproducts.
Hypoxic tumor specific toxicity with hypoxia selectivity expressed using hypoxia cytotoxicity ratio (HCR) concepts.
Support of a bystander effect via trigger/linker-mediated release of active alkylator over defined activation conditions and spatial distances.
Reduced normoxic toxicity.
Enhanced hypoxic cytotoxicity, including up to about 10^6-fold less toxic in normoxic cells and improvements reflected by hypoxia cytotoxicity ratio (HCR) measurements.
Documented Applications
Treating cancer in a patient in need of cancer treatment by administering a therapeutically effective dose of TH302.
Treating colorectal cancer.
Combination use in cancer treatment with paclitaxel.
Combination use in cancer treatment with gemcitabine.
Treating cancer, including therapy-resistant and metastatic cancer, using TH302 as a hypoxia-activated phosphoramidate alkylator prodrug.
Interested in licensing this patent?