Prodrugs and methods of use thereof
Inventors
Smaill, Jeffrey Bruce • Patterson, Adam Vorn • Ashoorzadeh, Amir • Guise, Christopher Paul • Mowday, Alexandra Marie • Ackerley, David Francis • Williams, Elsie May • Copp, Janine Naomi
Assignees
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Publication Number
US-10202408-B2
Publication Date
2019-02-12
Expiration Date
Abstract
The invention relates to compounds of use as targeted cytotoxic agents and methods of use thereof. In particular, the invention relates to prodrugs that are substantially resistant to human AKR1C3 enzyme metabolism, methods of cell ablation using said compounds and methods of treatment of cancer and other hyperproliferative disorders using said compounds.
Core Innovation
The invention relates to targeted cytotoxic prodrugs for treating cancer in a subject, including compounds described by Formula (I) and Formula (II). The prodrugs are designed to be substantially resistant to human AKR1C3-mediated aerobic off-mechanism activation, and the approach is positioned within directed enzyme prodrug therapy concepts including ADEPT, VDEPT, GDEPT, and CDEPT.
The problem addressed is unintended aerobic off-mechanism activation mediated by AKR1C3 compared with intended activation by nitroreductase pathways. The document discusses nitroreductase-activated prodrugs and motivates designs that resist AKR1C3-mediated aerobic activation, while targeting prodrug activation in a solid and/or hypoxic tumor context associated with nitroreductase activity.
The described invention uses aminated nitroaromatics prodrugs that include nitroaromatic prodrug intermediates and lead compounds, including compounds bearing fluoronitrobenzoic acid motifs and additional substituents such as ethylsulfonyl and phosphonooxy/phosphonoate-containing forms. The document presents specific compound examples such as 4-(ethylsulfonyl)-3-fluorobenzoic acid, fluoronitrobenzoic acids, tert-butyl esters, aminoethyl derivatives, bromoethyl substituted benzamides, piperazinyl methanones, and phosphate/phosphonooxy/phosphates, including named solid or salt forms such as methanesulfonate salts.
The prodrugs are intended for therapeutic administration to tumor cells or therapeutically proximate tumor cells in a subject, with claim-set focus on cancers selected from colon cancer, cervical cancer, or lung cancer. The document also supports nitroreductase substrate-validation and prodrug cytotoxicity screening concepts using parental versus nitroreductase-expressing cells, including evaluation of hypoxia/anoxia selectivity, resistance to AKR1C3 metabolism, multicellular-layer bystander killing, nitroreductase library screening, enzyme kinetics/rate assays, and in vivo xenograft efficacy showing tumor growth delay and radiation-combination benefits.
Claims Coverage
The independent claims are directed to methods for treating cancer, and in one independent claim a hyperproliferative condition, by administering defined nitroaromatic prodrug compounds in a solid and/or hypoxic tumor context. Across the independent claims, the main inventive features cover administering a Formula (I) compound or salt to tumor cells or near tumor cells for selected cancers, and administering a specified methanesulfonate salt to treat cancer or a hyperproliferative condition; additional features emphasize nitroreductase-linked activation or nitroreductase capability.
Administering formula (i) compound for hypoxic solid tumor treatment
Administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to a tumor cell, or therapeutically proximate to said tumor cell, in a solid and/or hypoxic tumor in a subject, wherein the cancer is selected from colon cancer, cervical cancer, or lung cancer.
Nitroreductase-linked activation in tumors
The tumor cells express nitroreductase.
Administering a specified methanesulfonate salt
Administering a therapeutically effective amount of the methanesulfonate salt of ((2 bromoethyl)(5 (4 ethylpiperazine 1 carbonyl) 2(methylsulfonyl)-4nitrophenyl)amino)ethyl methanesulfonate to a tumor cell, or therapeutically proximate to said tumor cell, in a solid and/or hypoxic tumor in the subject.
Nitroreductase enzyme capability or exogenous nitroreductase expression
Administering a compound together with either a nitroreductase enzyme capable of metabolizing the compound or a therapy that induces expression of an exogenous nitroreductase enzyme within or near a tumor.
The claim coverage centers on directed administration of nitroaromatic prodrug compounds in solid and/or hypoxic tumors, with one independent claim focused on a general Formula (I) for colon, cervical, or lung cancer and the other focused on a specifically named methanesulfonate salt for treating cancer or hyperproliferative conditions. The claims also connect treatment to nitroreductase expression or capability in or near tumors.
Stated Advantages
Compounds are designed to be substantially resistant to human AKR1C3-mediated aerobic off-mechanism activation.
Profound tumor growth delay and radiation-combination benefits in in vivo xenograft efficacy models with NfsA-expressing cell fractions and hypoxic/radiation-resistant tumors.
Hypoxia-selective cytotoxicity is evaluated as part of prodrug screening.
Resistance to AKR1C3 metabolism is evaluated.
Bystander killing mediated by bacterial nitroreductase (nfsA/nfsB) in multicellular layers is confirmed.
Documented Applications
Treating cancer by administering formula (I) compounds (or pharmaceutically acceptable salts) to tumor cells or therapeutically proximate tumor cells in a solid and/or hypoxic tumor in a subject, where the cancer is selected from colon cancer, cervical cancer, or lung cancer.
Treating cancer or a hyperproliferative condition by administering the specified methanesulfonate salt ((2 bromoethyl)(5 (4 ethylpiperazine 1 carbonyl) 2(methylsulfonyl)-4nitrophenyl)amino)ethyl methanesulfonate to tumor cells or therapeutically proximate tumor cells in a solid and/or hypoxic tumor in the subject.
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