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Tubulins are one of the oldest and most extensively studied therapeutic targets for cancer. Although many tubulin polymerizing and depolymerizing agents are known, the search for improved agents continues. We screened a class of tubulin targeting small molecules, and identified 4-(3,4,5-trimethoxylbenzoyl)-2-phenyl-thiazole (SMART-H) as our lead compound. SMART-H inhibited the proliferation of a variety of cancer cells in vitro, at sub-nanomolar IC50, and in vivo, in nude mice xenografts, with near 100% tumor growth inhibition. Metabolic stability studies with SMART-H in liver microsomes of four species (mouse, rat, dog, and human) revealed half-lives between < 5 and 30 min, demonstrating an inter-species variability. The clearance predicted based on in vitro data correlated well with in vivo clearance obtained from mouse, rat, and dog in vivo pharmacokinetic studies. SMART-H underwent four major metabolic processes, including ketone reduction, demethylation, combination of ketone reduction and demethylation, and hydroxylation in human liver microsomes. Metabolite identification studies revealed that the ketone and the methoxy groups of SMART-H were most labile, and that ketone reduction was the dominant metabolism reaction in human liver microsomes. We designed and tested four derivatives of SMART-H to improve the metabolic stability. The oxime and hydrazide derivatives, replacing the ketone site, demonstrated a 2-3-fold improved half-life in human liver microsomes, indicating that our prediction regrading metabolic stability of SMART-H can be extended by blocking ketone reduction. These studies led us to the next generation of SMART compounds with greater metabolic stability and higher pharmacologic potency.
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This article was published in the following journal.
Name: Drug metabolism and disposition: the biological fate of chemicals
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Agents that aid or increase the action of the principle drug (DRUG SYNERGISM) or that affect the absorption, mechanism of action, metabolism, or excretion of the primary drug (PHARMACOKINETICS) in such a way as to enhance its effects.
Naturally occurring genetic variations associated with drug response (e.g., dosage, extent and rate of metabolic processes). While these variants are not markers for GENETIC PREDISPOSITION TO DISEASE they influence PHARMACOKINETICS and pharmacodynamics and often occur on genes encoding drug metabolism enzymes and transporters (e.g., ANGIOTENSIN CONVERTING ENZYME; CYTOCHROME P-450 CYP2D6).
The action of a drug that may affect the activity, metabolism, or toxicity of another drug.
Forms to which substances are incorporated to improve the delivery and the effectiveness of drugs. Drug carriers are used in drug-delivery systems such as the controlled-release technology to prolong in vivo drug actions, decrease drug metabolism, and reduce drug toxicity. Carriers are also used in designs to increase the effectiveness of drug delivery to the target sites of pharmacological actions. Liposomes, albumin microspheres, soluble synthetic polymers, DNA complexes, protein-drug conjugates, and carrier erythrocytes among others have been employed as biodegradable drug carriers.
The properties and processes of drug metabolism and drug interactions.
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