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-9873710-B2
Publication Date
2018-01-23
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 treating cancer or a hyperproliferative condition by administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to tumor cells, or therapeutically proximate to said tumor cell, in a solid and/or hypoxic tumor in a subject. Formula (I) includes structural variables W, X, Y, Z, R, R1, R2, and n, with W and X representing Cl, Br, I, or OSO2R, Y representing H, CN, or SO2R, each R independently representing a lower C1-6 alkyl group, and n selected from 2 to 6.
The invention also includes nitrobenzamide mustard prodrugs and related formula (II) variants, including nitro-, sulfone-, bromoethyl-, phosphate-, and piperazine/substituted benzamide prodrug intermediates. The compounds include specified substituted 2-((2-bromoethyl)...)ethyl methanesulfonate variants and related phosphonooxyethyl/propyl carboxamide and hydroxyethyl/propyl carboxamide variants.
The compounds are associated with biological activation in tumor contexts, including nitroreductase activation and hypoxia-associated activation, with bystander effect and resistance related to AKR1C3 metabolism. The document also describes solubility performance targets and optional therapeutic combination concepts involving irradiation and enzyme prodrug therapy modalities such as GDEPT, VDEPT, CDEPT, and ADEPT.
Claims Coverage
The independent claim coverage centers on administering a structurally defined formula (I) compound to treat cancer or a hyperproliferative condition in solid and/or hypoxic tumor contexts. The merged claim set reflects six inventive features, with dependent refinements adding dose relative to maximum tolerated dose, tumor-cell nitroreductase expression, combination timing with irradiation and/or chemotherapeutic agents, specific salt selection, and named compound variants.
Formula (I) prodrug administration for tumor in solid and/or hypoxic environment
A method for treating cancer or a hyperproliferative condition comprising 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.
Defined structural substitution pattern for formula (I)
W represents Cl, Br, I, OSO2R and X represents Cl, Br, I, OSO2R, with Y representing H, CN, or SO2R, and each R independently representing a lower C1-6 alkyl group, where Z is selected from any of the radicals and * represents a point of attachment to formula (I).
Branched and alkyl substituent definitions on formula (I) core
R1 represents H or a lower C1-6 alkyl group; R2 represents H or a lower C1-6 alkyl group; and n is selected from 2 to 6, in the compound of formula (I).
Dose expressed relative to maximum tolerated dose
The method administers the compound such that the amount is about 20% to 100% of the subject’s maximum tolerated dose.
Tumor-cell nitroreductase expression requirement
The method is characterized in that the tumour cells express nitroreductase.
Combination with irradiation and/or other chemotherapeutic agents or therapies
The method is further defined as irradiating tumor cells and/or administering one or more chemotherapeutic agents and/or therapies to a subject before, during, or after administering compounds of formula (I).
Specific pharmaceutically acceptable methanesulfonate salt form
The claim set involves a pharmaceutically acceptable methanesulfonate salt form of the compound.
Selected named compound variants
The method is carried out using a compound selected from the listed substituted 2-((2-bromoethyl)...)ethyl methanesulfonate variants including compounds numbered 316, 317, 318, 319, 320, 321, 322, 323, 328, 329, 330, 331, 332, 333, 334, 335, 352, 353, 354, 359, 360, 361, 362, 363, 364, 365, and 366.
Overall, the claim coverage focuses on administering a structurally defined formula (I) compound to treat cancer or hyperproliferative conditions in solid and/or hypoxic tumor contexts. The dependent claims further narrow the approach by specifying dose range relative to maximum tolerated dose, requiring tumor-cell nitroreductase expression, enabling combination timing with irradiation and/or chemotherapeutic agents, and limiting to particular named compound variants, with additional refinement for specific salt selection.
Stated Advantages
Provides AKR1C3-resistant prodrugs to overcome off-mechanism aerobic activation by AKR1C3 and thereby reduce the loss of selectivity.
Enables targeted cytotoxicity for enzyme/prodrug cancer therapies including ADEPT, VDEPT, GDEPT, and CDEPT.
Provides a bystander effect in addition to direct tumor-cell cytotoxicity.
The compounds are associated with cell ablation/cancer treatment through nitroreductase activation and/or hypoxia-associated activation.
The document states solubility performance targets, including greater than 95 mM in PBS plus 2 equiv sodium bicarbonate and greater than 10 mM in lactate buffer pH 4.
The invention is positioned around enzyme-mediated activation, including nitroreductase-associated and AKR1C3/P450 reductase variants, and the resulting cytotoxic effects.
The described biological assessment includes tumor growth delay and enhanced killing with radiation under hypoxia models.
Documented Applications
Treating cancer or a hyperproliferative condition by administering Formula (I) compounds to tumor cells in a solid and/or hypoxic tumor in a subject.
Enzyme/prodrug cancer therapies including ADEPT, VDEPT, GDEPT, and CDEPT involving nitroreductase activation.
A combined treatment context involving irradiating tumor cells and/or administering one or more chemotherapeutic agents and/or therapies in temporal relation to administering Formula (I) compounds.
Targeting conditions where tumor cells express nitroreductase to support prodrug activation.
Biological screening and in vivo assessment of prodrug cytotoxicity, including comparison of parental versus nitroreductase-expressing cell lines.
Assessment of enzyme-linked activation under hypoxia-relevant conditions.
Multicellular layer (MCL) bystander killing and screening using bacterial nitroreductase library approaches with SOS reporter strains, including SOS GFP-based reporters.
In vivo assessment using a xenograft mouse model with tumor growth delay, bystander killing in mixed NfsA tumors, and enhanced killing with radiation under hypoxia models.
Optional therapeutic combination concepts involving irradiation and enzyme prodrug therapy modalities such as GDEPT, VDEPT, CDEPT, and ADEPT, including nitroreductase and encoding features (nfsA/nfsB, including E. coli).
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