The University of Kansas (KU) has a history of success in synthetic medicinal chemistry that continues to the present day. NIH investments in these activities have included a Chemical Methodologies and Library Development (CMLD) center and a Pilot Scale Library grant. With strong institutional support including a new building dedicated to probe discovery, we propose to marshal these resources in the service of the MLPCN as a Specialized Chemistry Center (SCC). The goals of the KU SCC will be to synthesize 10-15 collections of probe candidates per year, with each set containing between 100-300 discrete compounds in 20 mg quantities and >90% chemical purity as determined by HPLC (UV or ESL detection). In the past 15 months, we submitted over 1600 compounds that met these requirements to the MLSCN, comprising about a dozen different chemotypes. Thus, we are already functioning at the level comparable to that required for the SCC initiative and have developed a realistic plan for quickly undertaking the challenge of optimizing hits obtained from the MLPCN partnership. Strengths of the proposed program include (1) the demonstrated capability of producing small molecules in the quantities and purities demanded by MLPCN;(2) practical know-how of how to get compounds efficiently into the hands of biological collaborators, (3) demonstrated expertise in working with biological collaborators and optimizing compound potency and selectivity of a lead compound (and an outstanding set of consultants who will provide guidance on a monthly basis), (4) practical experience with parallel synthesis techniques and outstanding infrastructure for library production, (5) assignment to a brand-new laboratory containing 11 hoods in a new building extension that is dedicated to collaborative biomedical discovery (labs to be completed in 4/08), (6) strong cheminformatics expertise, (7) an experienced PI and an existing administrative structure that will facilitate the coordination of the project activities, (8) matching funds to provide essential major equipment and set up necessary laboratories for the SCC, and (9) a demonstrated commitment to the MLSCN. A Center-based research project is proposed to address the question of intracellular target identification for small molecule probes, an acknowledged roadblock in biomedical research. The goals of this project will be to (1) develop methodology for visualizing and identifying intracellular protein targets using fluorescent molecular probes and (2) develop yeast three-hybrid (Y3H) systems as tools for the identification of protein targets of small molecules.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HG005031-06
Application #
8528665
Study Section
Special Emphasis Panel (ZRG1-IFCN-K (52))
Program Officer
Schloss, Jeffery
Project Start
2008-09-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
6
Fiscal Year
2013
Total Cost
$1,863,000
Indirect Cost
$595,653
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Hackler, Amber; Patrick, Stephen L; Kahney, Elizabeth W et al. (2017) Antiparasitic lethality of sulfonamidebenzamides in kinetoplastids. Bioorg Med Chem Lett 27:755-758
Chattopadhyay, Debasish; Swingle, Mark R; Salter, Edward A et al. (2016) Crystal structures and mutagenesis of PPP-family ser/thr protein phosphatases elucidate the selectivity of cantharidin and novel norcantharidin-based inhibitors of PP5C. Biochem Pharmacol 109:14-26
Skarsfeldt, Mark A; Jepps, Thomas A; Bomholtz, Sofia H et al. (2016) pH-dependent inhibition of K?P3.1 prolongs atrial refractoriness in whole hearts. Pflugers Arch 468:643-54
Aflaki, Elma; Borger, Daniel K; Moaven, Nima et al. (2016) A New Glucocerebrosidase Chaperone Reduces ?-Synuclein and Glycolipid Levels in iPSC-Derived Dopaminergic Neurons from Patients with Gaucher Disease and Parkinsonism. J Neurosci 36:7441-52
Chung, Dong-Hoon; Golden, Jennifer E; Adcock, Robert S et al. (2016) Discovery of a Broad-Spectrum Antiviral Compound That Inhibits Pyrimidine Biosynthesis and Establishes a Type 1 Interferon-Independent Antiviral State. Antimicrob Agents Chemother 60:4552-62
Gui, Lin; Zhang, Xiaoyi; Li, Kelin et al. (2016) Evaluating p97 Inhibitor Analogues for Potency against p97-p37 and p97-Npl4-Ufd1 Complexes. ChemMedChem 11:953-7
Gold, Ben; Smith, Robert; Nguyen, Quyen et al. (2016) Novel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis. J Med Chem 59:6027-44
Roy, Sudeshna; Ĺ ileikyt?, Justina; Neuenswander, Benjamin et al. (2016) N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. ChemMedChem 11:283-8
Arshad, Mehreen; Goller, Carlos C; Pilla, Danielle et al. (2016) Threading the Needle: Small-Molecule Targeting of a Xenobiotic Receptor to Ablate Escherichia coli Polysaccharide Capsule Expression Without Altering Antibiotic Resistance. J Infect Dis 213:1330-9
Schroeder, Chad E; Neuenswander, Sarah A; Yao, Tuanli et al. (2016) One-pot, regiospecific assembly of (E)-benzamidines from ?- and ?-amino acids via an intramolecular aminoquinazolinone rearrangement. Org Biomol Chem 14:3950-5

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