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
Hammerlindl, Heinz; Ravindran Menon, Dinoop; Hammerlindl, Sabrina et al. (2018) Acetylsalicylic Acid Governs the Effect of Sorafenib in RAS-Mutant Cancers. Clin Cancer Res 24:1090-1102
Ecker, Brett L; Kaur, Amanpreet; Douglass, Stephen M et al. (2018) Age-Related Changes in HAPLN1 Increase Lymphatic Permeability and Affect Routes of Melanoma Metastasis. Cancer Discov :
CaƱadas, Israel; Thummalapalli, Rohit; Kim, Jong Wook et al. (2018) Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med 24:1143-1150
Grasso, Michael; Estrada, Michelle A; Berrios, Kiara N et al. (2018) N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK632) Promotes Inhibition of BRAF through the Induction of Inhibited Dimers. J Med Chem 61:5034-5046
Noguera-Ortega, Estela; Amaravadi, Ravi K (2018) Autophagy in the Tumor or in the Host: Which Plays a Greater Supportive Role? Cancer Discov 8:266-268
Jenkins, Russell W; Aref, Amir R; Lizotte, Patrick H et al. (2018) Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discov 8:196-215
Emptage, Ryan P; Lemmon, Mark A; Ferguson, Kathryn M et al. (2018) Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain. Structure 26:1137-1143.e3
Barnoud, Thibaut; Budina-Kolomets, Anna; Basu, Subhasree et al. (2018) Tailoring Chemotherapy for the African-Centric S47 Variant of TP53. Cancer Res 78:5694-5705
Liu, Shujing; Zhang, Gao; Guo, Jianping et al. (2018) Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis. Nat Commun 9:5426
Pathria, Gaurav; Scott, David A; Feng, Yongmei et al. (2018) Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival. EMBO J 37:

Showing the most recent 10 out of 144 publications