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 #
5R37CA031845-33
Application #
8477134
Study Section
Special Emphasis Panel (NSS)
Program Officer
Misra, Raj N
Project Start
1981-07-06
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
33
Fiscal Year
2013
Total Cost
$420,573
Indirect Cost
$147,060
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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Marsden, Matthew D; Wu, Xiaomeng; Navab, Sara M et al. (2018) Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents. Virology 520:83-93
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Fernandes-Cunha, Gabriella M; McKinlay, Colin J; Vargas, Jessica R et al. (2018) Delivery of Inorganic Polyphosphate into Cells Using Amphipathic Oligocarbonate Transporters. ACS Cent Sci 4:1394-1402
Haabeth, Ole A W; Blake, Timothy R; McKinlay, Colin J et al. (2018) mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice. Proc Natl Acad Sci U S A 115:E9153-E9161
Ryckbosch, Steven M; Wender, Paul A; Pande, Vijay S (2017) Molecular dynamics simulations reveal ligand-controlled positioning of a peripheral protein complex in membranes. Nat Commun 8:6
McKinlay, Colin J; Vargas, Jessica R; Blake, Timothy R et al. (2017) Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals. Proc Natl Acad Sci U S A 114:E448-E456
Wender, Paul A; Ebner, Christian; Fennell, Brandon D et al. (2017) Ynol Ethers as Ketene Equivalents in Rhodium-Catalyzed Intermolecular [5 + 2] Cycloaddition Reactions. Org Lett 19:5810-5813
Staveness, Daryl; Abdelnabi, Rana; Near, Katherine E et al. (2016) Inhibition of Chikungunya Virus-Induced Cell Death by Salicylate-Derived Bryostatin Analogues Provides Additional Evidence for a PKC-Independent Pathway. J Nat Prod 79:680-4
Pavlovic, Igor; Thakor, Divyeshsinh T; Vargas, Jessica R et al. (2016) Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo. Nat Commun 7:10622

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