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 #
5P01CA114046-07
Application #
8759679
Study Section
Special Emphasis Panel (ZCA1-RPRB-2)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
7
Fiscal Year
2014
Total Cost
$198,650
Indirect Cost
$56,878
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Webster, Marie R; Xu, Mai; Kinzler, Kathryn A et al. (2015) Wnt5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells. Pigment Cell Melanoma Res 28:184-95
Leu, Julia I-Ju; Zhang, Pingfeng; Murphy, Maureen E et al. (2014) Structural basis for the inhibition of HSP70 and DnaK chaperones by small-molecule targeting of a C-terminal allosteric pocket. ACS Chem Biol 9:2508-16
Vultur, A; Villanueva, J; Krepler, C et al. (2014) MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene 33:1850-61
Streib, Manuel; Kraling, Katja; Richter, Kristin et al. (2014) An organometallic inhibitor for the human repair enzyme 7,8-dihydro-8-oxoguanosine triphosphatase. Angew Chem Int Ed Engl 53:305-9
Ma, Xiao-Hong; Piao, Sheng-Fu; Dey, Souvik et al. (2014) Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest 124:1406-17
Zhang, Pingfeng; Leu, Julia I-Ju; Murphy, Maureen E et al. (2014) Crystal structure of the stress-inducible human heat shock protein 70 substrate-binding domain in complex with peptide substrate. PLoS One 9:e103518
Wang, Tao; Ge, Yingbin; Xiao, Min et al. (2014) SECTM1 produced by tumor cells attracts human monocytes via CD7-mediated activation of the PI3K pathway. J Invest Dermatol 134:1108-18
Malecka, Kimberly A; Fera, Daniela; Schultz, David C et al. (2014) Identification and characterization of small molecule human papillomavirus E6 inhibitors. ACS Chem Biol 9:1603-12
Licciulli, Silvia; Maksimoska, Jasna; Zhou, Chun et al. (2013) FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J Biol Chem 288:29105-14
Kastl, Anja; Dieckmann, Sandra; Wahler, Kathrin et al. (2013) Rhenium complexes with visible-light-induced anticancer activity. ChemMedChem 8:924-7

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