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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.
Oluwatoyin Asojo and Bin Zhan
“Hookworm Metabolome and Therapeutic Development”
We synthesized a series of ascarocide natural products and derivatives for screening against several proteins that Dr. Asojo is studying as potential vaccines for the prevention of human hookworm infection. Dr. Asojo has a hypothesis that the ascarocides may bind to and influence the biological activity of the proteins used in the vaccines.
Texas State University, Chemistry Department
“Mode of Action of the Amaryllidaceae Alkaloid Lycorine-Promising Anticancer Agent”
We have collaborated with Dr. Kornienko’s laboratory on several projects including the development and target identification of the anti-cancer alkaloid lycorine and derivatives of lapachol with potent cytotoxic activity. The CPRIT lab contributed to the design and synthesis of these interesting natural product derivatives. We prepared derivatives of the anticancer natural product lycorine for SAR studies and as cellular probes for mode of action determination.
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.
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 many of our collaborations, the CPRIT lab has prepared substrates for the enzymes under study in Dr. Glasner’s group and we continue to seek funding to support this interesting research area.