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
Kaur, Amanpreet; Webster, Marie R; Marchbank, Katie et al. (2016) sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532:250-4
Budina-Kolomets, Anna; Webster, Marie R; Leu, Julia I-Ju et al. (2016) HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors. Cancer Res 76:2720-30
Lu, Hezhe; Liu, Shujing; Zhang, Gao et al. (2016) Oncogenic BRAF-Mediated Melanoma Cell Invasion. Cell Rep 15:2012-24
Amaravadi, Ravi; Kimmelman, Alec C; White, Eileen (2016) Recent insights into the function of autophagy in cancer. Genes Dev 30:1913-30
Krepler, Clemens; Xiao, Min; Samanta, Minu et al. (2016) Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma. Oncotarget :
Grasso, Michael; Estrada, Michelle A; Ventocilla, Christian et al. (2016) Chemically Linked Vemurafenib Inhibitors Promote an Inactive BRAF(V600E) Conformation. ACS Chem Biol 11:2876-2888
Shannan, Batool; Chen, Quan; Watters, Andrea et al. (2016) Enhancing the evaluation of PI3K inhibitors through 3D melanoma models. Pigment Cell Melanoma Res 29:317-28
Jennis, Matthew; Kung, Che-Pei; Basu, Subhasree et al. (2016) An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev 30:918-30
Chatwichien, Jaruwan; Basu, Subhasree; Budina-Kolomets, Anna et al. (2016) PUMA-dependent apoptosis in NSCLC cancer cells by a dimeric β-carboline. Bioorg Med Chem Lett 26:4884-4887
Krepler, Clemens; Xiao, Min; Sproesser, Katrin et al. (2016) Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies. Clin Cancer Res 22:1592-602

Showing the most recent 10 out of 87 publications