Robert Hanzlik Research
- B.A., Chemistry and Biology, 1966, Southern Illinois University at Carbondale
- Ph.D., Organic Chemistry, 1970, Stanford University (E. E. van Tamelen)
- NSF/NATO Postdoctoral Fellow, Cambridge University, 1970-71 (Jack Lewis)
- NSF Fellow and Teaching Assistant, Stanford University, 1966-70
- NSF/NATO Postdoctoral Fellow, Cambridge University 1970-71
- Assistant Professor (1971-76), Associate Professor (1976-80), Professor (1980-present), Department of Medicinal Chemistry, University of Kansas
Current Teaching Activities
- MDCM 710 - Physiological Aspects of Medicinal chemistry
- MDCM 790 - Principles of Drug Design
- Frederick J. Di Carlo Distinguished Service Award, International Society for the Study of Xenobiotics, 2013
- Taito O. Soine Award in Medicinal Chemistry, University of Minnesota, 2012
- Leading Light Award, University of Kansas, 2012
- 40 Year Service Award, State of Kansas, 2012
- Awarded Honorary Life Membership by the International Society for the Study of Xenobiotics, 2001
- Excellence in Teaching Award, KU Center for Teaching Excellence, 1999
- Nelson Voldeng Memorial Lecturer, MALTO Medicinal Chemistry and Pharmacognosy Meeting, 1995
- Elected a Fellow of the American Association for Advancement of Science, 1994
- Invited Guest Lecturer, Eightieth Anniversary Celebration, Zhejiang Medical University, China, 1992
- Sato Memorial International Award, from the Foundation for Advanced Education in Science and the Pharmaceutical Society of Japan, 1991
- The Olin Petefish Research Award in the Basic Sciences, University of Kansas, 1989
- U. S. Honorary Ramsey Memorial Fellow, University of Cambridge, England, 1970-71
- NSF Fellow, Stanford University, 1966-70
- Graduated with Honors, Southern Illinois University, 1966. Outstanding senior chemistry major award, 1966. Outstanding senior zoology major award, 1965.
- Elected to membership in Phi Eta Sigma (1962), Phi Kappa Phi (1965), Rho Chi (1972), Sigma Xi (1972).
Chemical mechanisms of cytotoxicity.
Relatively simple organic molecules are sometimes capable of causing considerable toxicity to cells and tissues in vivo. Examples include solvents such as chloroform, bromobenzene and p-xylene, organosulfur compounds such as thioacetamide, thiobenzamide and the herbicide molinate, the analgesic drug acetaminophen, the common antioxidant BHT, and many others. The cytotoxicity of this diverse group of compounds stems from their common tendency to undergo biotransformation to chemically reactive metabolites which then covalently modify cellular proteins leading to cytotoxicity and even cell death. A major interest of our laboratory lies in the elucidation of the steps in this pathway, including identification of the reactive metabolites, the proteins they modify, the adduct structures formed, and their biochemical consequences for protein-protein interaction and signaling. Carefully designed "probe" molecules are synthesized, often with stable- or radio-isotope labeling, and their metabolism is investigated using state-of-the-art analytical methods. Adducted proteins are located on 2D gels by autoradiography and identified, along with their adducts, by modern methods of proteomic analysis based on HPLC/MS/MS.
Visit Chemical mechanisms of cytotoxicity for more information.
COBRE Center in Protein Structure and Function.
In addition to the research activities listed above, Dr. Hanzlik is the Principal Investigator and Director of a NIH Center of Biomedical Research Excellence in Protein Structure and Function. The center provides research support and mentoring to junior and senior faculty on four campuses in Kansas. The Center also hosts three service laboratories that are accessed by more than 75 different research groups across the country.
Visit COBRE Center in Protein Structure and Function for more information.
Completed Projects (no longer active)
(Name, dates, Thesis title, current or last known appointment)
- Greg O. Shearer (Ph.D., 1975), "A Mechanistic Study of Epoxidation by Cytochrome P-450 and Chemical Models."
- William H. Soine (Ph.D., 1978), "The Metabolism of Ferrocene and the Biological Activity of D,L-beta-Ferrocenyl-alpha-alanine." Professor of Medicinal Chemist (retired), Medical College of Virginia; Director of Pharmacy, VS Hospital, Richmond, VA
- John S. Walsh (M.S., 1979) "Studies on the Inhibition of Epoxide Hydrase." GlaxoSmithKline
- Kamlesh P. Vyas (co-directed Ph.D., 1979) Metabolism and Hepatotoxicity of Thiocarbonyl Compounds. Part I. Mechanism of Thiobenzamide-Induced Hepatotoxicity. Part II. Mechanism of alpha-Naphthylisothiocyanate-induced Hepatotoxocity. Merck Research Labs
- Richard B. Westkaemper (Ph.D., 1980), "Mechanistic Studies of Epoxide Hydrase and Related Model Reactions." Professor of Medicinal Chemistry, Medical College of Virginia
- John R. Cashman (Ph.D., 1982), "Toxicity, Metabolism and Chemistry of Thiobenzamide and Derivatives." President and CEO, Human BioMolecular Research Institute, San Diego, CA
- Stewart A. Thompson (Ph.D., 1983), "The Design, Synthesis and Evaluation of Peptide-Based Protease Inhibitors." Director of Formulation Development at Revance Therapeutics .
- Robert H. Tullman (Ph.D., 1984), "Inactivation of Cytochromes P-450 and Monoamine Oxidase by Cyclopropylamines. Evidence for Cation-Radical Intermediates." Head - Information and Quality Management at Novartis
- David A. Penney (co-directed Ph.D., 1984), "Part I. The Role of Metabolism in N-Methylthiobenzamide-Induced Pneumotoxocity. Part II. The Role of the Sympathetic Nervous System in Methylcyclopentadienyl Manganese Tricarbonyl-Induced Pneumotoxicity."
- Stephen P. Jacober (M.S., 1985), "Transition State Structures for the Enzymic Hydration of S- and R-p-Nitrostyrene Oxide." Boehringer-Ingelheim Pharmaceuticals
- K.-H. John Ling (M.S., 1987), "Kinetic Deuterium Isotope Effect on Phase-Transfer Catalyzed (PTC) Chlorination and Microsomal Hydroxylation of Xylenes." Allergan Corp.
- Larry R. Hall (Ph.D., 1989), "N-Dealkylation of Terriary Amides by Cytochrome P-450 and Anodic Oxidation." Bayer Animal Health
- Nicholas Andrew (M.S., 1990), "Secondary Deuterium Isotope Effects on Cytochrome P-450 Catalyzed Epoxidations." Director at Merck Sharp & Dohme
- Siming Liu, (Ph.D. 1991), "Design, Synthesis and Mechanistic Application of New Cysteine Proteinase Inhibitors." Senior Research Scientist and Director of MS Facilities, Georgia State University
- Jiang Zheng (Ph.D. 1992), "The Isolation and Identification of New Premercapturic and Mercapturic Acid Metabolites of Bromobenzene." Assoc. Professor and Principal Investigator, Seattle children's Hospital
- Pamela Riley, (Ph.D., 1993), "Arylcyclopropanes as Mechanistic Probes of Cytochrome P450-Catalyzed Benzylic Oxidations." Director of Scientific Development, Charles River Laboratories
- Hao Chen, (M.S., 1994), "Oxidation of Anilines and Anisoles with Cytochrome P450, Horseradish Peroxidase, Manganic Acetate and Ceric Bisulfate." Scientist, Forest Laboratories
- Shawn Harriman, 1991-96 (Ph.D. 5/96) "The Formation and Fate of Reactive Metabolic Intermediates." Director of Metabolism and Pharmacokinetics at Novartis Institutes for BioMedical Research Ping Lu, 1992-96 (M.S. 12/95) "Active Site Mapping of Cytochrome P4504A1 by means of Substrate-Based Inhibitors." Merck Research Labs
- Christopher L. Shaffer, 1996-2001 (Ph.D., 2001) "Enzymatic N-dealkylation of a Cyclopropylamine. Fate of the Cyclopropyl Moiety and Its Mechanistic Implications." (This thesis won the Graduate School Dissertation Prize for 2001-2). Associate Research Fellow at Pfizer Inc.
- Rheem A. Totah, 1997-2002 (PH.D., 2002) "Decarboxylation of Glycine Derivatives by a Peroxidase: A Mechanistic Study." Asst. Prof. of Medicinal Chemistry, University of Washington.
- Matthew A. Cerny, 1998-2005 (Ph.D., 2005) "Microsomal Metabolism of N-Benzyl-N-cyclopropylamine: Role of N-Oxidation in the Inactivation of Cytochromes P450." Boehringer-Ingelheim Pharmaceuticals
(Name, dates, last known position after KU)
- William J. Michaely, 1973-75
- Dale E. Williamson, 1974-76
- James M. Hilbert, 1976-77
- Vimal Kishore, 1976-77, Professor, Xavier University of Louisiana
- David W. Gottschall, 1981-83, Pfizer Animal Health, Kalamazoo, MI.
- John A. Buben, 1983-85, Eli Lilly & Co.
- Narayanan Narasimhan, 1983-88, Research Director, Ariad Pharmaceuticals
- Paul E. Weller, 1985-89, Research Manager, Roche Pharmaceuticals
- Jahangir Emrani, 1985-88
- Jayant Desai, 1987-88
- Donald E. Slaughter, 1989-91, Senior Investigator, Merck Research Labs
- Daniel V. Pratt, 1990-91, Assoc. Prof. of Chemistry, Graceland Univ., Lamoni, IA
- Mary Frauenhoff, 1990-91
- Chandra Chaurasia, 1992-94, Center for Drug Evaluation Research, U.S. Food & Drug Administration
- Ramesh Bambal, 1992-96, Senior Director and Head, Daiichi Sankyo India Pharma Pvt. Ltd. Ruye Xing, 1992-94,
- Elizabeth Rombach, 1992-98, Director of Quality Management Systems and Compliance at Catalent Pharma Solution
- Michail Alterman, 1993-95, Senior Investigator, Center for Biologics Evaluation Research, U. S. Food & Drug Administration Jian-she Kong, 1993-94, Senior Director of Process Chemistry at Bioduro, China
- Shankar Venkatraman, 1995-96, Merck Research Labs
- Sanjay Nimkar, 1996-97, Regulatory Affairs Manager at Hill's Pet Nutrition, Topeka KS
- Qingshan Li, 2001-03, Chief Scientific Officer, Captozyme Inc., Gainesville, FL
- Weimin Yue, 2001-05, Asst. Prof, Each China Univ. Sci. Technol., Shanghai
- Keisuke Ikehata, 2004-05, CNRL, University of Alberta, Canada
- Tao Ji, 2005-2007, Associate Scientist, Genentech
- Shanmugam Pachaiyappan, 2006-2008, Bangalore, India
- Diganta Sarma, 2009-2012, Assistant Professor, Dibrugarh University, India
- Gang Hu, 2009-2011, Research Associate in Pharmacology, University of Kansas
- Ke (Michael) Liu (2011-2012), Research Associate in Pharmacology, University of Pittsburg
Robert P. Hanzlik; Yakov M. Koen; Jianwen Fang, "Bioinformatic Analysis of 302 Reactive Metabolite Target Proteins. Which Ones Are Important for Cell Death?" Toxicological Sciences, 135, 390-401 (2013). PMID: 23897987
Yakov M. Koen, Diganta Sarma, Heather Hajovsky, Nadezhda A. Galeva, Todd D. Williams, Jeffrey L. Staudinger and Robert P. Hanzlik, "Protein Targets of Thioacetamide Metabolites in Rat Hepatocytes" Chem. Res. Toxicol. 26, 564−574 (2013). PMID: 23465048
Liz Hajovsky, Gang Hu, Yakov Koen, Diganta Sarma, Wenqi Cui, David S. Moore, Jeff L. Staudinger and Robert P. Hanzlik, "Metabolism and Toxicity of Thioacetamide and Thioacetamide S-Oxide in Rat Hepatocytes." Chem. Res. Toxicol. 25, 1955-1963 (2012). PMID: 22867114
Diganta Sarma, Heather Hajovsky, Yakov M. Koen, Nadezhda A. Galeva, Todd D. Williams, Jeffrey L. Staudinger, and Robert P. Hanzlik, "Covalent Modification of Lipids and Proteins in Rat Hepatocytes and in Vitro by Thioacetamide Metabolites." Chem. Res. Toxicol., 25, 1868–1877 (2012). PMID: 22667464
Yakov M. Koen, Heather Hajovsky, Ke Liu, Todd D. Williams, Nadezhda A. Galeva# Jeffrey L. Staudinger and Robert P. Hanzlik, "Liver Protein Targets of Hepatotoxic 4-Bromophenol Metabolites." Chem. Res. Toxicol. 25, 1777-1786 (2012). PMID: 22827705
Yakov M. Koen, Diganta Sarma,aTodd D. Williams, Nadezhda A. Galeva, R. Scott Obach and Robert P. Hanzlik, "Identification of Protein Targets of Reactive Metabolites of Tienilic Acid in Human Hepatocytes." Chem. Res. Toxicol. 25, 1145-54 (2012). PMID: 22462724
Diganta Sarma and Robert P. Hanzlik, "Synthesis of carbon-14, carbon-13 and deuterium labeled thioacetamide and thioacetamide S-oxide" Journal of Labelled Compounds and Radiopharmaceuticals, 54, 795-798 (2011). PMID: 22667464
Jianwen Fang, Yakov Koen and Robert P. Hanzlik, "Bioinformatic analysis of xenobiotic reactive metabolite target proteins and their interacting partners." BMC Chemical Biology 2009, 9:5 (12 June 2009). PMID: 19523227
M. A. Altaweel, J. VerHoeve, J. Eells, R. P. Hanzlik and B. Zhang, "Ocular and Systemic Safety Evaluation of Calcium Formate." J. Ocular Pharmacol. Toxicol. 25, 223-230 (2009). PMID: 19456257
Robert P. Hanzlik, Jianwen Fang, Yakov M. Koen, "Filling and Mining the Reactive Metabolite Target Protein Database," Chem.-Biol. Interactions, 179, 38-44 (2009). PMID: 18823962
Keisuke Ikehata, Tatyana G. Duzhak, Nadezhda A. Galeva, Tao Ji, Yakov M. Koen and Robert P. Hanzlik, "Protein Targets of Reactive Metabolites of Thiobenzamide in Rat Liver In Vivo." Chem. Res. Toxicol., 21, 1432-1442 (2008). PMID: 18547066
Weijun Huang, Yasufumi Yamamoto, Yi Li, Dengfeng Dou, Kevin R. Alliston, R. P. Hanzlik and W. C. Groutas, "An X-ray Snapshot of the Mechanism of Inactivation of Human Neutrophil Elastase by 1,2,5-Thiazolidin-3-one 1,1-Dioxide Derivatives, J. Med. Chem. 51, 2003-2008 (2008). PMID: 18318470
Robert P. Hanzlik, Yakov M. Koen, Bharga Theertham, Yinghua Dong and Jianwen Fang. "The reactive metabolite target protein database (TPDB) — a web-accessible resource." BMC Bioinformatics 8:95 (2007). PMID: 17367530
T. Ji, K. Ikehata, Y.M. Koen, S.W. Esch, T.D. Williams and R.P. Hanzlik, "Covalent Modification of Microsomal Lipids by Thiobenzamides in Vivo." Chem. Res. Toxicol. 20, 701-708 (2007). PMID: 17381136
Y.M. Koen, N.V. Gogichaeva, M.A. Alterman and R.P. Hanzlik, "A Proteomic Analysis of Bromobenzene Reactive Metabolite Targets in Rat Liver Cytosol." Chem. Res. Toxicol. 20, 511-519 (2007). PMID: 17305373
Y.M. Koen, W. Yue, N.A. Galeva, T.D. Williams and R.P. Hanzlik, "Site-Specific Arylation of Rat Glutathione S-Transferase A1 and A2 by Bromobenzene Metabolites In Vivo." Chem. Res. Toxicol. 19, 1426-1434 (2006). PMID: 17112229
Weimin Yue, Yakov M. Koen, Todd D. Williams, and Robert P. Hanzlik, "Use of Isotopic Signatures for Mass Spectral Detection of Protein Adduction by Chemically-Reactive Metabolites of Bromobenzene. Studies with Model Proteins." Chem. Res. Toxicol., 18, 1748-1754 (2005). PMID: 16300384
Membership in Professional Organizations
- American Association for Advancement of the Sciences (1966-present)
- American Chemical Society (1967-present)
- The Royal Society of Chemistry (1971-present)
- Society of Toxicology (1981-present)
- International Society for the Study of Xenobiotics (Charter Member, 1981-present)
- The Protein Society (2004-present)
Professional Service Activities
- Member, NIH Bioorganic and Natural Products Study Section, 1987-91.
- ad hoc Member, NIH Special Study Sections 1978, 1982, 1984, 1999, 2004, 2005, 2011, 2013.
- Member, Research Peer Review Committee, American Heart Association of Kansas, 1985-87.
- Gordon Conference on Drug Metabolism, Session Chairman 1979, Vice-Chairman 1983, Chairman 1984, Session Chairman 1994.
- American Chemical Society Tour Speaker: Gulf Coast Circuit, 1981; Texas Circuit, 1983.
- Society of Toxicology - Central States Chapter: Co-founder, 1984; Secretary-Treasurer, 1985-86; President, 1986-87.
- Society of Toxicology - Mechanisms Section: Vice-President Elect, 1985-86; Vice-President, 1986-87; President, 1987-88.
- International Society for the Study of Xenobiotics - Charter Member, 1981. Offices held: Councilor, 1984-87; First Chairman, Scientific Affairs Committee, 1986-1989; By-Laws Revision Committee, 1991; Publications Committee 1991-94; President-Elect 1994 and 1995; President 1996 and 1997; Past-President, 1998 and 1999. Service activities: Program Co-Chairman, First North American ISSX Symposium, 1985; Organized and Presented a Short-Course entitled "Reactive Metabolite Chemistry for Toxicologists" at the Second North American ISSX Meeting, 1987; Symposium Co-Organizer, Sixth North American ISSX Meeting, 1994; Program Committee, Fourth International ISSX Meeting, 1995; Session Organizer and Chair, Fourteenth North American Meeting, 2006.
- Member, Editorial Board, Xenobiotica, 1985-1991.
- Member, Editorial and Advisory Board, Molecular Pharmacology, 1986-90.
- Member, Editorial Advisory Board, Chemical Research in Toxicology, 1990-92.
- Member, Editorial Advisory Board, Life Sciences, 1993-2001.
- Member, Editorial Board, Toxicological Sciences, 1998-2001.
- Elected Member-at-Large for Pharmaceutical Sciences Section, AAAS, 2006-2010.
- Member, Editorial Advisory Board, Drug Metabolism and Disposition, 1994-present.