The proposed work is a continuation of a MERIT Award and involves the use of computer based design chemical synthesis, mechanistic biochemistry and chemical biology to design, synthesize and evaluate new compounds with novel structures , unique or novel modes of action, and clinical potential for the treatment of lymphoma, resistant cancer, cognitive dysfunction (e.g., Alzheimer's disease) and HIV/AIDS. Four projects are involved: bryostatin and bryologs, apoptolidins, new kinase inhibitor scaffolds for chemical genomics and molecular transporters for drug and probe delivery. Bryostatin is currently in clinical trials for cancer and Alzheimer's disease. Its supply is extremely limited and its clinical performance is non-optimal. New designed analogs are proposed that would address the supply problem and be tunable and potentially clinically superior as chemotherapeutic agents for the treatment of lymphoma and more generally cancer. Apoptolidin is among the most selective compounds in the NCI 60 cell line screen. New apoptolidins have been identified in our lab. Derivatives will be prepared to determine the basis for apoptolidin's exceptional selectivity and the activities of the new agents. Novel catalyst screening methodology will be used to exert reagent control over derivatization reactions. Ongoing studies on the mode of action of apoptolidins will be conducted. The design, synthesis, and evaluation of new scaffolds for kinase inhibition will be conducted with an emphasis on step economical access to novel, potent, and selective agents that could serve as leads for the development of new therapies. The scaffold design draws inspiration from therapeutic leads now in clinical trials. Molecular transporters, agents that enable or enhance cellular entry of molecules that by themselves would not enter cells or do so poorly, will be studied with an emphasis on their mode of cellular entry, selectivity and therapeutic value. A new strategy involving the use of transporters to overcome resistant cancer will be advanced and new drug conjugates prepared and evaluated to determine its generality. Studies on activatable transporters for targeted therapy are proposed. Studies on the use of transporters for adult stem and progenitor cell uptake will be conducted. Collectively this program is designed to advance science with an emphasis on creating new therapeutic opportunities.

Public Health Relevance

The propsed work involves the use of computer based design, chemical synthesis, and chemical biology to produce compounds with novel structures, unique modes of action and clinical potential for the treatment of lymphoma, resistant cancer, cognitive dysfunction (e.g., Alzheimer's diease), and HIV/AIDS. This work is intended to lead to transformative solutions to major health problems with an emphasis on cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA031845-32
Application #
8298519
Study Section
Special Emphasis Panel (NSS)
Program Officer
Misra, Raj N
Project Start
1981-07-06
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
32
Fiscal Year
2012
Total Cost
$445,327
Indirect Cost
$154,827
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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McKinlay, Colin J; Waymouth, Robert M; Wender, Paul A (2016) Cell-Penetrating, Guanidinium-Rich Oligophosphoesters: Effective and Versatile Molecular Transporters for Drug and Probe Delivery. J Am Chem Soc 138:3510-7
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Boudreault, Pierre-Luc; Mattler, Jennifer K; Wender, Paul A (2015) Studies on the regio- and diastereo-selective epoxidation of daphnanes and tiglianes. Tetrahedron Lett 56:3423-3427
Loy, Brian A; Lesser, Adam B; Staveness, Daryl et al. (2015) Toward a biorelevant structure of protein kinase C bound modulators: design, synthesis, and evaluation of labeled bryostatin analogues for analysis with rotational echo double resonance NMR spectroscopy. J Am Chem Soc 137:3678-85
Wender, Paul A; Jeffreys, Matthew S; Raub, Andrew G (2015) Tetramethyleneethane Equivalents: Recursive Reagents for Serialized Cycloadditions. J Am Chem Soc 137:9088-93
Wender, Paul A; Quiroz, Ryan V; Stevens, Matthew C (2015) Function through synthesis-informed design. Acc Chem Res 48:752-60
Vargas, Jessica R; Stanzl, Erika Geihe; Teng, Nelson N H et al. (2014) Cell-penetrating, guanidinium-rich molecular transporters for overcoming efflux-mediated multidrug resistance. Mol Pharm 11:2553-65

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