Metabolic and mechanistic exploration of a novel programmable genotoxicant against prostate cancer
Author(s)Morton, Charles Ingalls, IV
Massachusetts Institute of Technology. Dept. of Biological Engineering.
John M. Essigmann.
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Molecular design of novel pharmaceutical agents depends on a mechanistic paradigm. A library of compounds was designed to mimic some features of cisplatin that are believed to be in part responsible for its success as a chemotherapeutic agent against testicular cancer. The new compounds are designed to utilize proteins such as steroid receptors that are abnormally expressed in cancers to enhance toxicity and specificity. The synthetic phase of this project successfully produced a compound, 11P, that when tested against cancer cell lines demonstrated remarkable potency, including the induction of apoptosis in normally apoptosis-resistant prostate cancer lines. This drug candidate, comprising an aniline mustard tethered to a steroid moiety, is intended to form covalent adducts with DNA that, through association with the androgen receptor over-expressed in some prostate cancers, are likely to be shielded from repair, generating lethal crosslinks. Moreover, the titration of androgen receptor away from its normal function as a transcription factor may further inhibit tumor growth. While the mechanistic features of I1P are still under investigation, the potent anticancer activity warrants consideration of its possible clinical use, specifically against hormone-refractory, metastatic prostate cancer, for which current therapeutic options are extremely limited. One important step toward that goal involves characterizing the pharmacokinetics of the compound, including: a) understanding the rate of hydrolytic decomposition, b) evaluating the metabolic conversion by intracellular enzymes to active or inactive derivatives, and c) exploring the potential for contraindications between this drug candidate and other medications a prostate cancer patient may be taking concurrently. Herein are described the experiments that elucidate the pharmacokinetics of 1I1, showing that the drug candidate is a) subject to hydrolysis at rates that depend on the presence of plasma protein; b) extensively metabolized by the cytochromes P450 to products demonstrating reduced capacity for forming covalent adducts with DNA; and c) a potent inhibitor of the metabolism of known substrates of the 2D6 and 3A isoforms of cytochrome P450.
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2009.Vita. Cataloged from PDF version of thesis.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology