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.
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.
|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|
|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|
|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|
Showing the most recent 10 out of 101 publications