The primary objective of the Medicinal Chemistry Core of the Program Project is to facilitate the development of new drug candidates and tool compounds that will be used to increase our fundamental understanding of melanoma and to develop new treatments for melanoma, a disease for which effective chemotherapy is not currently available. The Medicinal Chemistry Core is well positioned to achieve this goal, providing support for each of the projects (2, 3 and 4) in which new chemical agents will be developed, and in which preliminary evaluation of the drug-like properties of these new entities will take place. Translational research requires access to certain chemistry resources starting from the earliest phases of both lead and target identification through drug development The capabilities of the Medicinal Chemistry Core exist in both organic chemistry (specifically organic synthesis), and medicinal chemistry (the design and evaluation of potent compounds with drug-like properties). The specific goals of the Core are: 1) To provide chemical synthesis and analytical support to the Program Projects;2) To design and synthesize small compound libraries based on preliminary biological hits;3) To provide synthesis of specialized labeled analogs for mechanism of action studies;4) To provide an evaluation of the drug-like properties of lead structures, starting with the characterization of pharmacologically active lead structures, to cheminformatics analysis, and the determination of ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles;and 5) To use the information obtained in Aim 4 to inform iterative optimization of lead structures, i.e., the design and synthesis of second- and third-generation candidate structures in which both drug-like properties and potency are optimized. This coordination will allow the Program Project investigators to most efficiently develop new chemical entities for biological evaluation as described in the different Projects. Currently, there are no centralized resources at Wistar or at the University of Pennsylvania for such efforts. The Medicinal Chemistry Core will provide superior chemistry facilities in a single location, with an efficient and streamlined mechanism for the synthesis and characterization of all of the compounds that will be used in each of the Projects. The result will not only foster increased collaboration and interaction among the participants in each of the Program Projects, but will also lead to considerable cost savings in this centralized Core facility.

Public Health Relevance

The Central role that the Medicinal Chemistry Core plays in the design and synthesis of all new compounds that will be evaluated for their potential as melanoma chemotherapeutics makes its public health relevance clear, since it will be the source of all new drug candidates that emerge from Projects 2, 3 and 4 in this Program.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA114046-06
Application #
8759656
Study Section
Special Emphasis Panel (ZCA1-RPRB-2 (M1))
Project Start
2013-09-25
Project End
2018-08-31
Budget Start
2013-09-25
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$232,523
Indirect Cost
$74,396
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhang, Ying; Kurupati, Raj; Liu, Ling et al. (2017) Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. Cancer Cell 32:377-391.e9
Frazier, Jason P; Bertout, Jessica A; Kerwin, William S et al. (2017) Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation. Cancer Res 77:2869-2880
Gade, Terence P F; Tucker, Elizabeth; Nakazawa, Michael S et al. (2017) Ischemia Induces Quiescence and Autophagy Dependence in Hepatocellular Carcinoma. Radiology 283:702-710
Taylor, Laura A; Abraham, Ronnie M; Tahirovic, Emin et al. (2017) High ALDH1 expression correlates with better prognosis in tumorigenic malignant melanoma. Mod Pathol 30:634-639
Garman, Bradley; Anastopoulos, Ioannis N; Krepler, Clemens et al. (2017) Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines. Cell Rep 21:1936-1952
Vitiello, Marianna; Tuccoli, Andrea; D'Aurizio, Romina et al. (2017) Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells. Oncotarget 8:25395-25417
Krepler, Clemens; Sproesser, Katrin; Brafford, Patricia et al. (2017) A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma. Cell Rep 21:1953-1967
Whelan, K A; Chandramouleeswaran, P M; Tanaka, K et al. (2017) Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance. Oncogene 36:4843-4858
Huang, Alexander C; Postow, Michael A; Orlowski, Robert J et al. (2017) T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60-65
Emptage, Ryan P; Schoenberger, Megan J; Ferguson, Kathryn M et al. (2017) Intramolecular autoinhibition of Checkpoint Kinase 1 is mediated by conserved basic motifs of the C-terminal Kinase Associated-1 domain. J Biol Chem :

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