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David G. Hangauer

Professor Emeritus
E-mail: hangauer@buffalo.edu

Education:

Ph.D., University at Buffalo, 1980 (Organic Chemistry)

Awards and Honors:

“Outstanding Inventor Award”, May 20, 2002 from the Research Foundation of the State of New York for “outstanding inventions from superior research at the State University of New York”.

STOR 2004 “Entrepreneur” award for starting Kinex Pharmaceuticals LLC.

STOR 2004 “Entrepreneur” award for starting Molecular Target Laboratories LLC.

STOR 2004 “Visionary Innovator” award bestowed on May 26, 2005 for inventing technology licensed to Kinex Pharmaceuticals LLC.

“Licensed Innovation Award”, Nov. 3, 2005 from the Research Foundation of the State of New York for innovations that led to licensing agreements between the Research Foundation and companies.

James H. Crowdle Award Medal, Feb. 2006. Award to an alumnus of the Canisius College Chemistry and Biochemistry Department that has made exceptional contributions to the field of chemistry and/or biochemistry.

2005 Visionary Innovator Award, June 2006, from the University at Buffalo in recognition of licensing my invention “Protection Against Noise Or Cancer Drug-Induced Hearing Loss Using Inhibitors of pp60-c-src Protein Tyrosine Kinase” to Kinex Pharmaceuticals, LLC.

2005 University at Buffalo Center for Advanced Biomedical and Bioengineering Technology Award, June 2006, in recognition of my collaboration with Kinex Pharmaceuticals, LLC on the research project “Development of a Src Inhibitor for the Treatment of Cancer”.

Niagara Frontier Intellectual Property Law Association and the Technical Societies Council of the Niagara Frontier Health Sciences 2006 Inventor of the Year for U.S. patent 7,070,936 entitled “Method for Designing Protein Kinase Inhibitors”. Award announced on April 18, 2007.

Business First’s Health Care 50 Award published in Business First’s April 2007 issue honoring extraordinary professionals involved in the medical field.

Chair’s Fellow for the 2007 Medicinal Chemistry Gordon Research Conference, Aug. 2007, Colby-Sayer College, New London, New Hampshire.

“Best Poster From An Academic Laboratory” 2007 Medicinal Chemistry Gordon Research Conference.

Niagara Frontier Intellectual Property Law Association and the Technical Societies Council of the Niagara Frontier Health Sciences 2007 Inventor of the Year for U.S. patent 7,300,931 entitled “Compositions for treating cell proliferation disorders”. This is the composition of matter and use patent for Kinex’s oncology drug KX2-391 currently in clinical trials. Award announced on May 8, 2008.

Niagara Frontier Intellectual Property Law Association and the Technical Societies Council of the Niagara Frontier 2007 Inventor of the Year across all categories (i.e. Independent Inventors, Life Sciences & Physical Sciences) for U.S. patent 7,300,931 entitled “Compositions for treating cell proliferation disorders”. This is the composition of matter and use patent for Kinex’s oncology drug KX2-391 currently in clinical trials. Award announced on May 8, 2008.

“Licensed Innovation Award”, April 2010 from the Research Foundation of the State of New York for innovations that led to licensing agreements between the Research Foundation and companies.

“Issued Patent Award” from the University at Buffalo in recognition of issued US Patent “PROTEIN-PROTEIN INTERACTION ANTAGONIST SCREENING LIBRARIES BASED UPON 1,4-DISUBSTITUTED NAPHTHALENES AND RELATED SCAFFOLDS” April 2011.

2012 University at Buffalo Faculty Entrepreneur of the Year.  June 13, 2012.  Award recognizes important role played in translating inventions and discoveries to benefit society—for patients with cancer and autoimmune diseases.

“2013 Honoree” Western New York American Cancer Society.

Specializations:

Structure-based-drug design, energetics of drug-receptor binding, discovery of drugs for cancer and autoimmune diseases, new drug discovery methods, strategies and applications in combinatorial chemistry, medicinal and synthetic organic chemistry.

Research Summary:

A broad-based peptide substrate directed protein kinase inhibitor discovery program was previously the focus of the lab from about 1990 and until about 2002. This project utilized computer-aided-drug design and combinatorial synthetic chemistry technologies in an iterative and complementary fashion. This research matured to the point that it was patented (US Patents 7,070,936 B1 & 7,005,445 B2) and a new biopharmaceutical company, Kinex Pharmaceuticals Inc. (www.kinexpharma.com), was formed based upon the technology. Compounds generated from the technology are progressing through clinical trials in cancer patients, and for other indications (e.g. KX2-391, US Patent 7,300,931). Our research at Kinex Pharmaceuticals has now broadened to include the discovery of new drugs for immunology associated diseases. As this research progressed at Kinex Pharmaceuticals it was phased out of the University at Buffalo lab.  I took a half time leave of absence from my faculty position in 2010-2011 and then a full time leave of absence from my faculty position in 2012-2013 to increase my efforts as Kinex Pharmaceuticals Chief Scientific Officer (CSO).  I then formally retired from my faculty position in 2013 to continue as Kinex’s CSO full time.  Nevertheless our University at Buffalo fundamental research program described below continued as the publication list shows.

Molecular recognition between proteins and their ligands in an aqueous environment is a fundamental process in biology. A more complete and detailed chemical characterization of this process is needed to better understand and predict the geometry, and more particularly the strength, of ligand-protein binding. These fundamentals also extend beyond protein-ligand binding into molecular recognition in biological systems more generally.  We are attempting to systematically dissect the ligand binding energetics into enthalpy, entropy, enthalpy/entropy compensation, desolvation and cooperativity components. Our approach utilizes: 1) structure-based analog design to address specific questions, 2) synthesis of the analogs, 3) characterization of the binding process with biochemical assays for the free energy of binding, isothermal calorimetry (ITC) to dissect out the enthalpy and entropy of binding, surface plasma resonance for on and off rates (Biacore), x-ray crystallography of the bound complexes to establish binding mode, and computations such as molecular dynamics to gain additional insights beyond the experimental data. More details can be obtained by reviewing the selection of our publications on this topic provided below.

Selected Publications:

  1. Christof Gerlach, Michael Smolinski, Holger Steuber, Christoph A. Sotriffer, Andreas Heine, David Hangauer* and Gerhard Klebe*,“Thermodynamic inhibition profile of a cyclopentyl- and a cyclohexyl derivative towards thrombin: The same, but for different reasons”, Angew. Chem. Int. Ed., 46(44), 8511-8514 (2007).
  2. Bernhard Baum, Menshawy Mohamed, Mohamed Zayed, Christof Gerlach, Andreas Heine, David Hangauer* and Gerhard Klebe*,“More than a simple lipophilic contact: A detailed thermodynamic analysis of nonbasic residues in the S1-pocket of thrombin”, Journal of Molecular Biology, 390(1), 56-69 (2009).
  3. Bernhard Baum, Laveena Muley, Andreas Heine, Michael Smolinski, David Hangauer* and Gerhard Klebe*,“Think twice: Understanding the high potency of bis-phenyl methane inhibitors of thrombin”, Journal of Molecular Biology, 391(3), 552-564 (2009).
  4. Laveena Muley, Bernhard Baum, Michael Smolinski, Marek Freindorf, Andreas Heine, Gerhard Klebe* and David G. Hangauer*, “Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: Synthesis, modeling and molecular dynamics simulations of a congeneric series of thrombin inhibitors”, J. Med. Chem., 53, 2126-2135 (2010).
  5. Bernhard Baum, Laveena Muley, Michael Smolinski, Andreas Heine, David Hangauer* and Gerhard Klebe*, “Non-additivity of functional group contributions in protein-ligand binding: A comprehensive study by crystallography and isothermal titration calorimetry”, Journal of Molecular Biology, 397(4), 1042-1054 (2010).
  6. Englert, A. Biela, M. Zayed, A. Heine, D. Hangauer* and G. Klebe*, “Displacement of disordered water molecules from hydrophobic pocket creates enthalpic signature: Binding of phosphoramidate to the S1’-pocket of thermolysin”, Biochimica et Biophysica Acta, General Subjects, 1800(11), 1192-1202 (2010).
  7. Tobias Brandt, Nicole Holzmann, Laveena Muley, Maan Khayat, Christof Wegscheid-Gerlach, Bernhard Baum, Andreas Heine, David Hangauer* and Gerhard Klebe*, “Congeneric but still very distinct: How closely-related ligands can experience very different thermodynamic and structural properties towards trypsin”, Journal of Molecular Biology 405(5), 1170-1187 (2011).
  8.  Biela, A.; Khayat, M.; Tan, H.; Kong, J.; Heine, A.; Hangauer, D.*; Klebe, G.*, “Impact of Ligand and Protein Desolvation on Ligand Binding to the S1 Pocket of Thrombin”, Journal of Molecular Biology, 418(5), 350-366 (2012).
  9. Nasief, Nader N.*; Tan, Hongwei; Kong, Jing; Hangauer, David G.*, “Water Mediated Ligand Functional Group Cooperativity: The Contribution of a Methyl Group to Binding Affinity is Enhanced by a COO- Group Through Changes in the Structure and Thermodynamics of the Hydration Waters of Ligand-Thermolysin Complexes”, Journal of Medicinal Chemistry, 55, 8283-8302 (2012).
  10. Biela, Adam; Nasief, Nader N.; Betz, Michael; Heine, Andreas; Hangauer, David*; Klebe, Gerhard*, “Dissecting the Hydrophobic Effect on the Molecular Level: The Role of Water, Enthalpy, and Entropy in Ligand Binding to Thermolysin”, Angewandte Chemie, International Edition, 52(6), 1822-1828 (2013).
  11. Nasief*, Nader N.; Hangauer*, David, “Influence of Neighboring Groups on the Thermodynamics of Hydrophobic Binding: An Added Complex Facet to the Hydrophobic Effect”, Journal of Medicinal Chemistry, 57(6), 2315-2333 (2014).
  12. Nader N. Nasief*, David Hangauer*, “Additivity or cooperativity: Which model can predict the influence of simultaneous incorporation of two or more functionalities in a ligand molecule?”,   European Journal of Medicinal Chemistry, 90, 897-915 (2015).
  13. Ahmed M. Said * and David G. Hangauer *, “Binding Cooperativity Between a Ligand Carbonyl Group and a Hydrophobic Side Chain Can be Enhanced by Additional H-bonds in a Distance Dependent Manner: A Case Study With Thrombin Inhibitors”, European Journal of Medicinal Chemistry, in press, DOI: 10.1016/j.ejmech.2015.03.059 (2015).