This renewal application involves synthetic, mechanistic, mode of action, computer modeling, and biochemical studies directed at the design, synthesis, biological evaluation and development of new cancer chemotherapeutic leads and of new drug delivery systems. These studies seek to advance our understanding of the molecular basis for the selective regulation of protein kinase C (PKC), targets of interest in cancer chemotherapy, to develop novel and practical synthetic approaches to promising chemotherapeutic leads, especially those that exhibit new modes of action, and more generally compounds of interest in cancer and medical research, and to advance an exciting new class of transporters for drug and probe delivery. Section D.1 describes a continuation of plans using computer assisted design, synthesis, and biological assays including real time translocation studies of PKC fusion proteins for the study of the daphnane gnidimacrin, a new and promising cancer chemotherapeutic lead that operates through a novel mechanism putatively involving the regulation of cell cycling through the selective modulation of PKC. Section D.2 describes our complementary efforts to access synthetically and broadly the chemotherapeutically promising members of the daphnane family and to begin to elucidate the basis for their unusual potency and therapeutically promising biological activity. Section D.3 describes plans for the synthesis and biological evaluation of daphnane-tigliane hybrids, a totally new structural class of potential therapeutic leads designed to probe factors that control selective translocation of PKC. Section D.4 describes plans for the advancement of our studies on laulimalide, a cancer chemotherapeutic lead that functions like taxol but binds to a novel microtubule site and exhibits therapeutically promising activity against taxol resistant cancer cell lines. Section D.5 describes plans to identify new molecular transporters, to evaluate their performance in real time in an in vivo assay of tissue selective entry and to explore a new concept for tissue selective entry of molecular transporters based on tissue activatable transporters.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031841-26
Application #
7030994
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
1981-07-01
Project End
2010-04-30
Budget Start
2006-06-01
Budget End
2007-04-30
Support Year
26
Fiscal Year
2006
Total Cost
$317,558
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
McKinlay, Colin J; Benner, Nancy L; Haabeth, Ole A et al. (2018) Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters. Proc Natl Acad Sci U S A 115:E5859-E5866
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
Khan, Tapan K; Wender, Paul A; Alkon, Daniel L (2018) Bryostatin and its synthetic analog, picolog rescue dermal fibroblasts from prolonged stress and contribute to survival and rejuvenation of human skin equivalents. J Cell Physiol 233:1523-1534
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
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
Benner, Nancy L; Zang, Xiaoyu; Buehler, Daniel C et al. (2017) Vault Nanoparticles: Chemical Modifications for Imaging and Enhanced Delivery. ACS Nano 11:872-881
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
Hsu, Hsiao-Tieh; Trantow, Brian M; Waymouth, Robert M et al. (2016) Bioorthogonal Catalysis: A General Method To Evaluate Metal-Catalyzed Reactions in Real Time in Living Systems Using a Cellular Luciferase Reporter System. Bioconjug Chem 27:376-82

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