CPT-11 is a camptothecin derived prodrug that is activated by carboxylesterases (CE) to yield SN-38, a potent topoisomerase I inhibitor. CPT-11 has demonstrated remarkable antitumor activity in animal models and is currently being used in clinical trials for a variety of human malignancies. The drug is activated in the liver and primarily excreted by deposition in the bile. However, the dose limiting toxicity for this drug is delayed diarrhea that occurs 24-96 hours following administration. Since the bile duct opens into the gut in the duodenum, the region of the intestine that demonstrates the highest levels of CE and CPT-11 converting activity, we propose that the diarrhea occurs via drug activation from the human intestinal CE (hiCE) present in the gut. In an attempt to ameliorate this toxicity, we have developed selective hiCE inhibitors. In this application, we will use a variety of molecular modeling and QSAR techniques to improve the potency of these compounds and determine the mechanism of enzyme inhibition by these novel chemicals. Finally, we will assess the efficacy of these agents towards reducing CPT-11-induced diarrhea in an animal model.
The Specific Aims of this application are therefore to: 1) design and synthesize selective inhibitors based upon SAR analysis; 2) determine the mechanism of inhibition; 3) assess the ability of the novel inhibitors to selectively inhibit hiCE both in vitro and in cell culture systems; 4) generate a mouse model that results in expression of the hiCE cDNA under control of the mouse intestinal CE promoter; and 5) determine whether the novel inhibitors ameliorate CPT-11-induced diarrhea in this mouse model. Overall, these studies should allow development of selective inhibitors for use in combination with CPT-11 to reduce the toxicity of the drug. Additionally, such compounds may allow dose intensification of CPT-11 for improved cancer therapy.
|Hatfield, M Jason; Chen, Jingwen; Fratt, Ellie M et al. (2017) Selective Inhibitors of Human Liver Carboxylesterase Based on a ?-Lapachone Scaffold: Novel Reagents for Reaction Profiling. J Med Chem 60:1568-1579|
|Wierdl, Monika; Tsurkan, Lyudmila; Hatfield, M Jason et al. (2016) Tumour-selective targeting of drug metabolizing enzymes to treat metastatic cancer. Br J Pharmacol 173:2811-8|
|Argikar, Upendra A; Potter, Philip M; Hutzler, J Matthew et al. (2016) Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance. AAPS J 18:1391-1405|
|Hatfield, M Jason; Umans, Robyn A; Hyatt, Janice L et al. (2016) Carboxylesterases: General detoxifying enzymes. Chem Biol Interact 259:327-331|
|Hatfield, M Jason; Tsurkan, Lyudmila G; Hyatt, Janice L et al. (2013) Modulation of esterified drug metabolism by tanshinones from Salvia miltiorrhiza (""Danshen""). J Nat Prod 76:36-44|
|Kasai, Kazue; Nakashima, Hiroshi; Liu, Fang et al. (2013) Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs. Mol Ther Nucleic Acids 2:e113|
|Yu, Xiaozhen; Sigler, Sara C; Hossain, Delwar et al. (2012) Global and local molecular dynamics of a bacterial carboxylesterase provide insight into its catalytic mechanism. J Mol Model 18:2869-83|
|Kim, Jin-Ki; Yuan, Hong; Nie, Jingxin et al. (2012) High payload dual therapeutic-imaging nanocarriers for triggered tumor delivery. Small 8:2895-903|
|Hatfield, M Jason; Potter, Philip M (2011) Carboxylesterase inhibitors. Expert Opin Ther Pat 21:1159-71|
|Parkinson, Elizabeth I; Jason Hatfield, M; Tsurkan, Lyudmila et al. (2011) Requirements for mammalian carboxylesterase inhibition by substituted ethane-1,2-diones. Bioorg Med Chem 19:4635-43|
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