Synthesis of a Kidney Cancer Drug

UC RiversideBiologyMedicine
DOI: 10.18258/0426
$5,112
Raised
102%
Funded on 6/07/13
Successfully Funded
  • $5,112
    pledged
  • 102%
    funded
  • Funded
    on 6/07/13

About This Project

We need to prepare a 75 mg sample of our anti-kidney cancer drug for testing. The sample was requested by the National Cancer Institute for study against human kidney tumors implanted into mice.

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What is the context of this research?

This project will support the preparation of a 75 mg sample of our drug candidate TIR-199 that was requested by the National Cancer Institute for a mouse study. The work must be initiated by the end of May, and the testing of the compound will be performed at the NCI following. The results of that testing should be available by the end of the year. Contributions will be tax-deductible because they will go to the Regents of the University of California.

What is the significance of this project?

This project is important because it supports our novel natural product-based drug lead, which the National Cancer Institute’s Developmental Therapeutics Program has shown selectively kills a particular type of kidney cancer cell. Their Biological Evaluation Committee nominated it for the next level of testing, assays vs. human tumor cells grown in hollow fibers and implanted into mice. They are particularly interested in TIR-199 because of its selectivity vs. kidney cancer and the absence of many other good drugs against this cancer. This drug was synthesized in small quantities in our lab originally and tested in the lab of our biology collaborator Bachmann, showing sufficient promise that the NCI was willing to study it in their famous 60-cell panel. The results with TIR-199 in that panel led to its nomination for next-stage testing, and the NCI has requested quantities of drug sufficient to support that testing. The mode of action of TIR-199 is as an inhibitor of the proteasome, a relatively new type of cancer drug. Only two FDA-approved drugs, bortezomib and carfilzomib, have this mode of action, and they are used against multiple myeloma, not kidney cancer. Our natural drug was recently announced at the 5th International Conference on Drug Discovery and Therapy, held in Dubai (UAE). Information on that talk is given here: http://ucrtoday.ucr.edu/12020

We have the right team, not only to do this project, but to carry it forward following the completion of the NCI study. This team has been working together for several years in this broad project area and has several peer-reviewed publications on their work. It includes two academics with diverse backgrounds, Prof. Michael Pirrung of UC-Riverside and Prof. André Bachmann of the University of Hawaii and Cancer Center of Hawaii. The Pirrung lab synthesized TIR-199, among many other cancer drug candidates. Bachmann did the initial biological testing of TIR-199. He also has very good experience in translational cancer research, particularly another new class of agents, polyamine inhibitors. He gives our team the ability to take the results from the NCI studies and plan the next steps for moving TIR-199 into pre-clinical and clinical studies.

The postdoc who would be supported under this project is Dr. Sudhakar Ambadi. He has worked in the PI’s lab for the last 2.5 years on the proteasome inhibitor project, and he is a co-author on publications from our lab on this topic. This project needs support now because the PI’s lab does not have current grant funds to support the re-synthesis of this drug sample, or this project at all, actually. As a consequence, Dr. Ambadi has been given a layoff notice effective at the end of May. Though he was not the first person to synthesize TIR-199, Dr. Ambadi did prepare the amount of drug we currently have. He thus has the ideal background and experience to perform the re-synthesis. He will be supervised day-to-day in this endeavor by Prof. Pirrung, who has decades of experience in this type of synthesis.

What are the goals of the project?

A month’s postdoctoral stipend is sought to support Dr. Ambadi’s ongoing work. We already have a synthesis of TIR-199 that works, and we used it to prepare a ~25 mg sample of drug already in hand. However, another 50 mg of drug is needed for the NCI to begin the studies they have planned. The synthesis will certainly work, as it is already proven; it requires 12 steps from chemicals we can purchase, which is reasonable to achieve in the month requested. We have no doubt about success in the preparation of this quantity of drug, considering we have done all of those specific synthetic steps before. Lab members also have several years of experience in the preparation of compounds in this chemical family, using methods similar to those reported in our first publication on the synthesis of these natural product proteasome inhibitors, which appeared in 2010.

Budget

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The budget will be used to support Dr. Ambadi's salary for the month that will be required to prepare this sample of TIR-199, plus it will pay for the raw materials needed for the synthesis.

Meet the Team

Michael Pirrung
Michael Pirrung
Distinguished Professor of Chemistry

Affiliates

University of Texas, Austin, September 1973-December 1975 B.A. in Chemistry with Highest Honors. University of California, Berkeley, September 1976-June 1980 Ph.D. in Organic Chemistry (with C. H. Heathcock). Columbia University, 1980-81 NSF Postdoctoral Fellow in Organic Chemistry (with G. Stork).
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Team Bio

Michael Pirrung was trained as a synthetic organic chemist via academic studies at UT-Austin, UC-Berkeley, and Columbia University. His first faculty position was in the chemistry department at Stanford in the early 80s. In the late 1980s, he joined a working group of scientists forming a then-new company, Affymax. He established the chemistry program at Affymax, focusing on new methods of creating chemical diversity. His work there included the co-invention of microarrays, and he has been called “der Vater des DNA-Chips”. His Science paper on this work was recognized with the 1991 AAAS-Newcomb Cleveland Prize and, two decades later, is in the top 1% of most highly cited papers worldwide. The patent family based on his 1992 microarray patent US 5,143,854 was in the top ten most cited patent families during 1999-2004. This patent estate also led to his receiving the 1993 Intellectual Property Owners Distinguished Inventor Award, the 2004 Chemical Pioneer Award of the American Institute of Chemists, and the 2006 European Inventor of the Year (for small and medium-sized enterprises). He has been a visiting professor at UC-Berkeley, Baylor College of Medicine, Oxford, UC-San Diego, UC-Irvine and Caltech. He has held Hertz, Sloan, and Guggenheim fellowships and a NSF Presidential Young Investigator Award. In 1990, Pirrung joined Duke University, where he founded and directed the University Program in Biological Chemistry and Biotechnology for Business, an educational outreach program for non-scientists. In 2004 he joined the UC-Riverside Chemistry department as UC Presidential Chair and in 2012 was named Distinguished Professor. His current research emphasizes organic synthesis and combinatorial chemistry. He has over 160 peer-reviewed publications and over 40 US and international patents, and has authored five books.

Michael Pirrung

Michael Pirrung was trained as a synthetic organic chemist via academic studies at UT-Austin, UC-Berkeley, and Columbia University. His first faculty position was in the chemistry department at Stanford in the early 80s. In the late 1980s, he joined a working group of scientists forming a then-new company, Affymax. He established the chemistry program at Affymax, focusing on new methods of creating chemical diversity. His work there included the co-invention of microarrays, and he has been called “der Vater des DNA-Chips”. His Science paper on this work was recognized with the 1991 AAAS-Newcomb Cleveland Prize and, two decades later, is in the top 1% of most highly cited papers worldwide. The patent family based on his 1992 microarray patent US 5,143,854 was in the top ten most cited patent families during 1999-2004. This patent estate also led to his receiving the 1993 Intellectual Property Owners Distinguished Inventor Award, the 2004 Chemical Pioneer Award of the American Institute of Chemists, and the 2006 European Inventor of the Year (for small and medium-sized enterprises). He has been a visiting professor at UC-Berkeley, Baylor College of Medicine, Oxford, UC-San Diego, UC-Irvine and Caltech. He has held Hertz, Sloan, and Guggenheim fellowships and a NSF Presidential Young Investigator Award. In 1990, Pirrung joined Duke University, where he founded and directed the University Program in Biological Chemistry and Biotechnology for Business, an educational outreach program for non-scientists. In 2004 he joined the UC-Riverside Chemistry department as UC Presidential Chair and in 2012 was named Distinguished Professor. His current research emphasizes organic synthesis and combinatorial chemistry. He has over 160 peer-reviewed publications and over 40 US and international patents, and has authored five books.

Additional Information

The outcome of these in vivo antitumor studies will be incorporated into a publication being planned by Profs. Pirrung and Bachmann that will incorporate all facets of their project to this stage, including the chemical synthesis of TIR-199, its direct action against the proteasome, its cell-based cancer-killing action, and specific markers of its mode of action and the basis for its cancer cell selectivity. The project will also be discussed at scientific meetings attended by and in seminars given by Prof. Pirrung. The most obvious product that could result from this project would be a FDA-approved drug for use against kidney cancer. The data and results of this project will certainly be shared widely with the public, subject of course to the protection of whatever intellectual property they might entail, which is essential to enable a novel drug to enter commercial development. Donors of >$100 to this project will receive formal acknowledgement in all peer-reviewed publications resulting from it, thanking either the individual or the organizational donation. The acknowledgement will read “We thank XX, YY, and ZZ for supporting this research through a generous donation on Microryza”. I will also acknowledge such donation at all conferences/talks that I am presenting this work, including logos if desired.

Project Backers

  • 23Backers
  • 102%Funded
  • $5,112Total Donations
  • $88.00Average Donation
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