Philip Potter, PhD

Philip M. Potter, PhD

Associate Member, St. Jude Faculty

Departments

Chemical Biology & Therapeutics

Contact Information

Philip Potter, PhD
Chemical Biology & Therapeutics
MS 230, Room D-3022E
St. Jude Children's Research Hospital
262 Danny Thomas Place
Memphis, TN 38105-3678
Phone: (901) 595-2825
FAX: (901) 595-4293

Education

PhD - University of Manchester, Manchester, England


Research Interests

  • Enzyme prodrug therapy
  • Esterase-mediated drug catalysis
  • Tumor-specific gene expressions

Activation of CPT-11

Selective inhibition of carboxylesterases

Structures of carboxylesterases


Selected Publications

Hemmert A, Otto T, Wierdl M, Edwards CC, Fleming C, Potter PM, Cerasoli DM, Redinbo MR. Human carboxylesterase 1 stereoselectively binds the nerve agent cyclosarin and spontaneously hydrolyzes the nerve agent sarin. Mol Pharmacol 2010 (in press).

Hatfield MJ, Tsurkan L, Hyatt JL, Yu X, Edwards CC, Hicks LD, Wadkins RM, Potter PM. Biochemical and molecular analysis of carboxylesterase-mediated hydrolysis of cocaine and heroin. Br J Pharmacol 2010 (in press).

Crow JA, Herring K, Xie S, Potter PM, Ross MK. Inhibition of the carboxylesterase activity of THP1 cell lysate and recombinant human carboxylesterase 1 by oxysterols and fatty acids. Biochim Biophys Acta - Molecular and Cell Biology of Lipids 1801:31-41, 2010.

Hicks LD, Hyatt JL, Stoddard S, Tsurkan L, Edwards CC, Wadkins RM, Potter PM. Improved, selective human intestinal carboxylesterase inhibitors designed to modulate 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (irinotecan; CPT-11) toxicity. J Med Chem 52:3742-3752, 2009.

Lu X, Howard MD, Talbert DR, Rinehart JJ, Potter PM, Jay M, Leggas M. Nanoparticles containing anti-inflammatory agents as chemotherapy adjuvants II: Stability in plasma. Am Assoc Pharm Sci J 11:120-122, 2009.

Harada T, Nakagawa Y, Wadkins RM, Potter PM, Wheelock CE. Comparison of benzil analog- and trifluoromethyl ketone (TFK)-mediated carboxylesterase inhibition specificity using classical and 3-D quantitative structure activity relationship analysis. Bioorg Med Chem 17:149-164, 2009.

Crow JA, Middleton BL, Borazjani A, Hatfield MJ, Potter PM, Ross MK. Inhibition of carboxylesterase 1 enhances cholesteryl ester accumulation within monocytes/macrophages. Biochim Biophys Acta 1781:643-654, 2008.

Hatfield MJ, Wierdl M, Potter PM. Modifications of human carboxylesterase for improved prodrug activation. Expert Opin Drug Metab Toxicol 4:1153-1165, 2008.

Barthel BL, Torres RC, Hyatt JL, Edwards CC, Hatfield MJ, Potter PM, Koch TH. Activation of pentyl PABC-doxazolidine, a carbamate-containing prodrug of doxazolidine, by human intestinal carboxylesterase. J Med Chem 51:298-304, 2008.

Hyatt JL, Moak T, Hatfield JM, Tsurkan L, Edwards CC, Wierdl M, Danks MK, Wadkins RM, Potter PM. Selective inhibition of carboxylesterases by isatins (indole-2,3-diones). J Med Chem 50:1876-1885, 2007.

Wierdl M, Tsurkan L, Hyatt JL, Hatfield MJ, Edwards CC, Danks MK, Redinbo MR, Potter PM. An improved human carboxylesterase for use in enzyme/prodrug therapy with CPT-11. Cancer Gene Ther 15:183-192, 2008.

Streit TM, Borazjani A, Lentz SE, Wierdl M, Potter PM, Gwaltney SR, Ross MK. Evaluation of the ‘side-door’ in carboxylesterase-mediated catalysis and inhibition. Biol Chem 389:149-162, 2008.

Hyatt JL, Wadkins RM, Tsurkan L, Hicks L, Hatfield MJ, Edwards CC, Ross CR, Cantalupo SA, Crundwell G, Guy RK, Potter PM. Planarity and constraint of the carbonyl groups in 1,2-diones are determinants for selective inhibition of human carboxylesterase 1. J Med Chem 50:5727-5734, 2007.

Hicks LD, Hyatt JL, Moak T, Edwards CC, Tsurkan L, Wierdl M, Ferreira A, Wadkins RM, Potter PM. Analysis of the inhibition of mammalian carboxylesterases by novel fluorobenzoins and fluorobenzils. Bioorg Med Chem 15:3801-3817, 2007.

Fleming CD, Edwards CC, Potter PM, Cerasoli DM, Kirby SD, Maxwell DM, Redinbo MR. Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and Tabun. Biochemistry 46:5063-5071, 2007.

Crow JA, Borazjani A, Potter PM, Ross MK. Hydrolysis of pyrethroids by human and rat tissues: Examination of intestinal, liver and serum carboxylesterases. Toxicol Appl Pharmacol 221:1-12 2007.

Wadkins, RM, Hyatt JL, Edwards CC, Tsurkan L, Redinbo MR, Wheelock CE, Jones PD, Hammock BD,  Potter PM. Analysis of trifluoromethylketone-mediated inhibition of mammalian carboxylesterases. Mol Pharmacol 71:713-723, 2007.

Danks MK Yoon KJ,  Bush RA, Remack JS, Wierdl M, Tsurkan L, Kim SU, Garcia E, Metz M, Najbauer J, Potter PM, Aboody KS, Tumor-targeted enzyme/prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma. Cancer Res 67:22-25, 2007.

Aboody KS, Bush RA, Garcia E, Metz M, Najbauer J, Justus KA, Phelps DA, Remack JS, Yoon KJ, Gillespie S, Kim SU, Glackin C, Potter PM, Danks MK. Development of a tumor-selective approach to treat metastatic cancer. PLoS One 1:e23; 1-10, 2006. Editorial PLoS Medicine 3:e482, 2182-2183, 2006.

Bencharit S, Edwards CC, Morton CL, Howard-Williams EL, Kuhn P, Potter PM, Redinbo MR. Multisite promiscuity in the processing of endogenous substrates by human carboxylesterase 1. J Mol Biol 363:201-214, 2006.

Potter PM, Wadkins RM. Carboxylesterases - detoxifying enzymes and targets for drug therapy. Curr Med Chem 13:1045-1054, 2006.

Godin SJ, Scollon EJ, Hughes MF, Potter PM, DeVito MJ Ross MK. Species difference in the in vitro metabolism of deltamethrin and esfenvalerate: Differential oxidative and hydrolytic metabolism by humans and rats. Drug Metab Dispos 34:1764-1771, 2006.

Hyatt JL, Tsurkan L, Wierdl M, Edwards CC, Danks MK, Potter PM. Intracellular inhibition of carboxylesterases by benzil: Modulation of CPT-11 cytotoxicity. Mol Cancer Therap 5:2281-2288, 2006.

Yoon KJ, Qi J, Remack JS, Virga KG, Hatfield J, Potter PM, Lee RE, Danks MK. Development of an etoposide prodrug for dual prodrug-enzyme antitumor therapy. Mol Cancer Therap 5:1577-1584, 2006.

Ross MK, Borazjani A, Edwards CC, Potter PM. Hydrolytic metabolism of pyrethroids by human and other mammalian carboxylesterases. Biochem Pharmacol 71: 657-669, 2006.

Harel M, Hyatt JL, Brumshtein B, Morton CL, Wadkins RM, Silman I, Sussman JL, Potter PM. The 3D structure of the anticancer prodrug CPT-11 with Torpedo californica acetylcholinesterase rationalizes its inhibitory action on AChE and its hydrolysis by butyrylcholinesterase and carboxylesterase. Chem Biol Int 157-158:153-157, 2005.

Fleming CF, Bencharit S, Edwards CC, Hyatt JL, Morton CL, Howard-Williams EL, Potter PM, Redinbo MR. Structural insights into drug processing by human carboxylesterase 1: tamoxifen, mevastatin, and inhibition by benzil. J Mol Biol 352:165-177, 2005.

Hyatt JL, Stacy V, Wadkins RM, Yoon KJ, Wierdl M, Edwards CC, Crundwell G, Potter PM. Inhibition of carboxylesterases by benzil and heterocyclic analogs dependent upon the aromaticity of the ring and flexibility of the dione moiety. J Med Chem 48:5543-5550, 2005.

Wierdl M, Potter PM. Update on gene therapy approaches for cancer. Current Hematology Reports 4:294-299, 2005.

Tyminski E, LeRoy S, Terada K, Hyatt JL, Danks MK, Potter PM, Saeki Y, Chiocca EA. Brain tumor oncolysis with replication-conditional HSV1 expressing the prodrug-activating genes, CYP2B1 and secreted hiCE, in combination with cyclophosphamide and irinotecan. Cancer Res 65:6850-6857, 2005.

Harel M, Hyatt JL, Brumshtein B, Morton CL, Yoon KJP, Wadkins RM, Silman I, Sussman JL, Potter PM. The crystal structure of the complex of the anticancer prodrug CPT-11 with Torpedo acetylcholinesterase provides a molecular explanation for its cholinergic action. Mol Pharmacol 67:1874-1881, 2005.

Hyatt JL, Tsurkan L, Morton CL, Harel M, Brumshtein B, Silman I, Sussman JL, Wadkins RM, Potter PM. Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11. Chem Biol Int 157-158:247-252, 2005.

Wadkins RM, Hyatt JL, Wei X, Yoon KJP, Wierdl M, Edwards CC, Morton CL, Obenauer JC, Damodaran K, Beroza P, Danks MK, Potter PM. Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases. J Med Chem 48:2906-2915, 2005.

Redinbo MR, Potter PM. Mammalian Carboxylesterases: From drug targets to protein therapeutics. Drug Discov Today 10:313-325, 2005.

Morton CL, Iacono L, Hyatt JL, Taylor KR, Cheshire PJ, Houghton PJ, Danks MK, Stewart CF, Potter PM. Metabolism and antitumor activity of CPT-11 in plasma esterase-deficient mice. Cancer Chemother Pharmacol 56:629-636, 2005.

Yoon KJ, Potter PM, Danks MK. Development of prodrugs for enzyme-mediated, tumor-selective therapy. Curr Med Chem AntiCancer Agents 5:107-113, 2005.

Yoon KJ, Hyatt JL, Krull EJ, Morton CL, Lee RE, Potter PM, Danks MK. Characterization of inhibitors of specific carboxylesterases: development of compounds for translational application. Mol Cancer Therap 3:903-909, 2004.

Wadkins RM, Hyatt JL, Yoon KJ, Morton CL, Lee RE, Damodaran K, Beroza P, Danks MK, Potter PM. Identification of novel selective human intestinal carboxylesterase inhibitors for the amelioration of CPT-11 induced diarrhea: Synthesis, QSAR analysis, mechanism of action and biological activity. Mol Pharmacol 65:1336-1343, 2004.

Wierdl M, Morton CL, Nguyen, N, Redinbo MR, Potter PM. Molecular modeling of CPT-11 metabolism by carboxylesterases: Use of pnb CE as a model. Biochemistry 43:1874-1882, 2004.

Stubdhal H, Perin N, Lemmon M, Holman P, Bauzon M, Potter PM, Danks MK, Fattaey A, Dubensky T, Johnson L. A prodrug strategy using ONYX-015-based replicating adenoviruses to deliver rabbit liver carboxylesterase to tumor cells for conversion of CPT-11 to SN-38. Cancer Res 63:6900-6908, 2003.

Yoon KJ, Krull EJ, Morton CL, Bornmann WG, Lee RE, Potter PM, Danks MK. Activation of a novel camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure activity relationship and docking studies. Mol Cancer Therap 11:1171-1181, 2003.

Redinbo MR, Bencharit S, Potter PM. Human carboxylesterase 1: From drug metabolism to drug discovery.  Biochem Society Trans 31:620-624, 2003.

Yoon KJ, Morton CL, Potter PM, Danks MK, Lee RE. Synthesis and evaluation of esters and carbamates to identify critical functional groups for esterase-specific metabolism. Bioorganic Medicinal Chem 11:3237-3244, 2003.

Wierdl M, Wall A, Morton CL, Danks MK, Schuetz JD, Potter PM. Carboxylesterase-mediated sensitization of human tumor cells to CPT-11 cannot override BCRP-mediated drug resistance. Mol Pharm 64:279-288, 2003.

Bencharit S, Morton CL, Hyatt, JL, Kuhn P, Danks MK, Potter PM, Redinbo MR. Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: From binding promiscuity to selective inhibition. Chem and Biol 10:341-349, 2003. Preview, Chem and Biol 10:295-297, 2003.

Bencharit S, Morton CL, Xue Y, Potter PM, Redinbo MR. Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme. Nat Struct Biol 10:349-356, 2003.

Wierdl M, Morton CL, Harris LC, Danks MK, Schuetz JD, Potter PM. p53-Mediated regulation of expression of a rabbit liver carboxylesterase confers sensitivity to CPT-11. J Pharmacol Exp Ther 304:699-705, 2003.

Wagner LM, Guichard SM, Burger RA, Straign CM, Ashmun RA, Harris LC, Houghton PJ, Wierdl M, Potter PM, Danks MK. Targeting gene therapy: application to autologous stem cell grafts. Cancer Res 62:5001-5007, 2002.

Sompop B, Morton CL, Howard-Williams EL, Danks MK, Potter PM, Redinbo MR. Structural insights into CPT-11 activation by mammalian carboxylesterases. Nature Struct Biol 9:337-342, 2002.

Iyengar RV, Pawlik CA, Krull EJ, Phelps DA, Harris LC, Potter PM, Danks MK. Use of a modified ornithine decarboxylase promoter to achieve efficient c-MYC or N-MYC-regulated protein expression. Cancer Res 61:3045-3052, 2001.

Wierdl M, Morton CL, Weeks J, Danks MK, Harris LC, Potter PM. Sensitization of human tumor cells to CPT-11 via adenoviral-mediated delivery of a rabbit liver carboxylesterase. Cancer Res 61:5078-5082, 2001.

Meck M, Wierdl M, Wagner L, Burger R, Harris LC, Potter PM, Danks MK. A VDEPT approach to purging neuroblastoma cells from hematopoeitic cells using adenovirus encoding rabbit carboxylesterase and CPT-11. Cancer Res 61:5083-5089, 2001.

Wadkins R, Morton CL, Weeks JK, Oliver L, Wierdl M, Danks MK, Potter PM. Structural constraints affect the metabolism of CPT-11 by esterases. Mol Pharmacology 60:355-362, 2001.

Potter PM, Danks MK. Carboxylesterase-mediated activation of irinotecan. Cancer Res Alert 2:80-83, 2000.

Khanna R, Morton CL, Wierdl M, Danks MK, Potter PM. Proficient metabolism of CPT-11 by a human intestinal carboxylesterase. Cancer Res 60:4725-4728, 2000.

Morton CL, Wierdl M, Oliver L, Ma M, Danks MK, Stewart CF, Eiseman JL, Potter PM. Activation of CPT-11 in mice: Identification and analysis of a highly effective plasma esterase. Cancer Res 60:4206-4210, 2000.

Pawlik CA, Iyengar RV, Krull EJ, Speigel J, Khanna R, Harris LC, Potter PM, Danks MK, Guichard,S. N-MYC-mediated overexpression of a rabbit liver carboxylesterase sensitizes neuroblastoma cells to CPT-11. Mol Therapy 1:457-463, 2000.

Morton CL, Potter PM. Comparison of Escherichia coli, Saccharomyces cerevisiae, Pichia pastoris, Spodoptera frugiperda and COS7 cells for recombinant gene expression: Application to a rabbit liver carboxylesterase. Mol Biotechnology 16:193-202, 2000.

Potter PM, McKenzie PP, Husain N, Morton CL, Harris LC Construction of adenovirus for high level expression of small RNAs in mammalian cells: Application to a Bcl-2 ribozyme. Mol Biotechnology 15:105-114, 2000.

Wierdl M, Morton CL, Danks MK, Potter PM. Isolation and characterization of a cDNA encoding a horse butyrylcholinesterase: Evidence for CPT-11 activation. Biochem Pharmacol 59:773-781, 2000.

Wadkins RM, Potter PM, Vladu B, Marty J, Mangold G, Weitman S, Manikumar G, Wani MC, Wall ME, Von Hoff DD. Water soluble 20(S)-glycinate esters of 10,11,methylene dioxycamptothecins are highly active against human breast cancer xenografts. Cancer Res 59:3424-3428, 1999.

Danks MK, Morton CL, Krull EJ, Cheshire PJ, Richmond LB, Naeve CW, Pawlik CA, Houghton PJ, Potter PM. Comparison of activation of CPT-11 by rabbit and human carboxylesterase for use in enzyme/prodrug therapy. Clin Cancer Res 5:917-924, 1999.

Morton CL, Wadkins R, Danks MK, Potter PM: The anticancer drug CPT-11 is a potent inhibitor of acetylcholinesterases but is activated to SN-38 by butyrylcholinesterases. Cancer Res 59:1458-1463, 1999.

Danks MK, Morton CL, Pawlik CA, Potter PM: Overexpression of a rabbit liver carboxylesterase sensitizes human tumor cells to CPT-11. Cancer Res 58:20-2, 1998.

Guichard S, Morton CL, Krull EJ, Stewart CF, Danks MK, Potter PM: Conversion of the CPT-11 metabolite APC to SN-38 by rabbit liver carboxylesterase. Clin Cancer Res 4:3089-94, 1998.

Potter PM, Pawlik CA, Morton CL, Naeve CW, Danks MK. Isolation and partial characterization of a cDNA encoding a rabbit liver carboxylesterase that activates the prodrug CPT-11. Cancer Res 58:2646-2651, 1998.

Potter PM, Wolverton JS, Morton CL, Wierdl M, Danks MK. Cellular localization domains of a rabbit and a human carboxylesterase: influence on CPT-11 metabolism by the rabbit enzyme. Cancer Res 58:3627-3632, 1998.

Last update: January 2010

 

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