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The CPRIT lab is a collaboration center with synthetic organic/medicinal chemistry expertise serving as an interface between bioactive small molecule/natural product identification and cell biology/mode of action studies for drug discovery. We would be interested in future collaborations, including grant proposals, if you need synthetic organic chemistry or reaction screening and optimization support for one of your projects. Please contact us:
Phone: (254) 710-2162
CURRENT COLLABORATORS | PAST COLLABORATORS
Bill Plunkett and Rong Chen
“Development of Derivatives of Pateamine A for the treatment of B-Cell Malignancies”
We are currently developing several new derivatives of Pateamine A for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell malignancies either alone or in mechanism-based combination. The new analogs are more potent than DMDAPatA and possess lower plasma protein binding. DMDAPatA and the new derivatives bind to eukaryotic initiation factor 4A (eIF4A) and inhibit protein translation which is a relatively new target for anticancer therapy. CLL presents a unique model to test inhibitors of eIF4A. First, the CLL cells are characterized by the critical dependence on the sustained expression of Mcl-1 for survival. Thus, apoptosis is induced rapidly upon removal of Mcl-1 protein. Second, Mcl-1 is one of the top four eIF4F transcripts (MYC, MCL-1, BCL-XL and CCND1). Because of the greater degree of complexity in the secondary structure within their 5’-untranslated region, their translation is highly dependent on the helicase activity of eIF4A. Third, Mcl-1 is intrinsically short-lived due to two PEST sequences that program its protein for ubiquitylation and proteosomal degradation, thus its level is very sensitive to inhibitors of protein biosynthesis.
Yoel Kashman and Jun Liu
“Derivatization of Salarin C for mode-of-action studies”
Salarin C is a marine natural product isolated from the Madagascar Fascaplysinopsis sp. sponge collected in Salary Bay. It has potent cytotoxic activity against more than 60 cell lines tested in vitro and it induces apoptosis in a dose and time dependent manner. Dr. Kashman and his group have elucidated the structure-activity relationships (SAR) with Salarin C. We are preparing probe derivatives of the natural product in an effort to determine its mode-of-action and identify the biological target to which it binds in collaboration with Dr. Jun Liu’s lab.
Texas A&M University:
James Smith Profile page
“Occidifungin: derivatives for mode-of-action determination”
Occidiofungin is a cyclic glycolipopeptide produced by a soil bacterium called Burkholderia contaminans MS14 and has been reported to have a wide spectrum of activity against several fungal species. A novel antifungal compound is needed to complement current chemotherapeutic treatments. There are very few choices in the clinic for the treatment of serious fungal infections. Azoles, polyenes, and echinocandins are marketed under a variety of different names, but have relatively few unique mechanisms of action, such as inhibition of ergosterol production, binding ergosterol, and target glucan synthesis, respectively. Furthermore, currently approved antifungal agents have limitations in their spectrum of activity and are becoming ineffective due to resistance. Occidiofungin is active against zygomycetes, dermatophytes, yeast, and Cryptococcus species and is able to inhibit fungi resistant to clinically used antifungal agents. An alkyne derivative of the natural product was prepared and used to determine that the natural product binds to F- and G-actin and causes aggregation of the F-actin filaments leading to apoptosis. Further studies to understand how binding to actin leads to apoptosis are underway.
“Comparative Mechanisms of Cancer Prevention”
The genesis of this project dates back 30 years to a program focused on the anticancer mechanisms of indole-3-carbinol (I3C), 3,3’-diindoylmethane (DIM) and related dietary indoles. A programmatic shift occurred when the research team discovered the histone deacetylate (HDAC) inhibitory actions of another compound from cruciferous vegetables, namely sulforaphane (SFN), which put the work at the interface of epigenomics, diet, and cancer prevention. One of the fundamental principles governing this research is that, unlike the genetic changes in cancer that are essentially irreversible, epigenetic mechanisms are potentially modifiable by our diet and lifestyle. Based on mechanistic studies in cell-based assays, experiments in preclinical models, and data from human trials, the research moved into new directions focused on the role of epigenetic readers/writers/erasers and the expression and processing of RNAs. The CPRIT lab will use our toolkit of reactions to prepare biotin tagged derivatives of metabolites of sulforaphane (SFN) and indole-3-carbinol (I3C) that were previously and continue to be identified. Additionally, if the bioactive metabolite is not commercially available, the CPRIT Lab will develop a synthetic process to prepare metabolites.
Dr. Raushel studies the fundamental principles involved in enzyme-catalyzed chemistry. The CPRIT lab has synthesized inhibitors and substrates of the enzymes of interest to Dr. Raushel’s group so they can study the mechanism and function of these interesting proteins.
Margaret E. Glasner
Dr. Glasner is interested in understanding the relationship between enzyme structure and function. Her group studies how catalytic promiscuity serves as a starting point for evolving new enzyme activities. Like the Raushel collaboration above, the CPRIT lab has prepared substrates for the enzymes under study in Dr. Glasner’s group.