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Andrew Wiemer


andrew.wiemer@gmail.com
Mentor: Raymond Hohl, M.D./Ph.D.
Lab Phone: 335-8272

Targeting GTPases in Cancer through Bisphosphonate-Induced Depletion of Specific Isoprenoids

Targeting GTPases in Cancer through Bisphosphonate-Induced Depletion of Geranylgeranyl Diphosphate

The isoprenoid biosynthetic pathway can be defined as the series of enzymatic reactions that produce sterols and other large isoprenoids from hydroxymethylglutaryl CoA. Flux through this pathway produces a series of isoprenoid diphosphate intermediates, some of which are incorporated post-translationally into proteins in a process called protein prenylation. One key metabolite is the 20-carbon geranylgeranyl diphosphate (GGPP), which is produced by the enzyme GGPP synthase. My collaborators have produced a library of bisphosphonate-containing isoprenoid analogs. I identified for the first time that many of these compounds are potent and specific inhibitors of GGPP synthase, and then established the relative potencies of these compounds for both in vitro and cellular inhibition of GGPP synthase. I also studied the cellular internalization of these compounds and the relative efficacy of pro-drug analogs. Finally, I have defined the cellular consequences of GGPP synthase inhibition in the context of multiple isoprenoid feedback mechanisms. I am currently focused on determining the efficacy of GGPP synthase inhibition in mouse xenograft cancer models.

Tong H, Wiemer AJ, Neighbors JD, Hohl RJ. Quantitative determination of farnesyl and geranylgeranyl diphosphate levels in mammalian tissue. Anal Biochem. 2008 Jul 15;378(2):138-43. Epub 2008 Apr 15. PubMed PMID: 18457649.

Wiemer AJ, Yu JS, Shull LW, Barney RJ, Wasko BM, Lamb KM, Hohl RJ, Wiemer DF. Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation. Bioorg Med Chem. 2008 Apr 1;16(7):3652-60. Epub 2008 Feb 8. PubMed PMID: 18308574.

Dudakovic A, Wiemer AJ, Lamb KM, Vonnahme LA, Dietz SE, Hohl RJ. Inhibition of geranylgeranyl diphosphate synthase induces apoptosis through multiple mechanisms and displays synergy with inhibition of other isoprenoid biosynthetic enzymes. J Pharmacol Exp Ther. 2008 Mar;324(3):1028-36. Epub 2007 Dec 14. PubMed PMID:18083912.

Wiemer AJ, Yu JS, Lamb KM, Hohl RJ, Wiemer DF. Mono- and dialkyl isoprenoid bisphosphonates as geranylgeranyl diphosphate synthase inhibitors. Bioorg Med Chem. 2008 Jan 1;16(1):390-9. Epub 2007 Sep 18. PubMed PMID: 17905588.

Maalouf MA, Wiemer AJ, Kuder CH, Hohl RJ, Wiemer DF. Synthesis of fluorescently tagged isoprenoid bisphosphonates that inhibit protein geranylgeranylation. Bioorg Med Chem. 2007 Mar 1;15(5):1959-66. Epub 2007 Jan 4. PubMed PMID: 17254791.

Mente NR, Wiemer AJ, Neighbors JD, Beutler JA, Hohl RJ, Wiemer DF. Total synthesis of (R,R,R)- and (S,S,S)-schweinfurthin F: differences of bioactivity in the enantiomeric series. Bioorg Med Chem Lett. 2007 Feb 15;17(4):911-5. Epub 2006 Dec 12. PubMed PMID: 17236766.

Wiemer AJ, Tong H, Swanson KM, Hohl RJ. Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase. Biochem Biophys Res Commun. 2007 Feb 23;353(4):921-5. Epub 2006 Dec 21. PubMed PMID: 17208200.

Shull LW, Wiemer AJ, Hohl RJ, Wiemer DF. Synthesis and biological activity of isoprenoid bisphosphonates. Bioorg Med Chem. 2006 Jun 15;14(12):4130-6. Epub 2006 Mar 6. PubMed PMID: 16517172.

Kim M, Kleckley TS, Wiemer AJ, Holstein SA, Hohl RJ, Wiemer DF. Synthesis and activity of fluorescent isoprenoid pyrophosphate analogues. J Org Chem. 2004 Nov 26;69(24):8186-93. PubMed PMID: 15549786.

Chen X, Wiemer AJ, Hohl RJ, Wiemer DF. Stereoselective synthesis of the 5'-hydroxy-5'-phosphonate derivatives of cytidine and cytosine arabinoside. J Org Chem. 2002 Dec 27;67(26):9331-9. PubMed PMID: 12492335.

Jung KY, Hohl RJ, Wiemer AJ, Wiemer DF. Synthesis of phosphonate derivatives of uridine, cytidine, and cytosine arabinoside. Bioorg Med Chem. 2000 Oct;8(10):2501-9. PubMed PMID: 11058045.

Abstracts

Yu, J.S., Wiemer, A.J., Lamb, K.M., Hohl, R.J., and Wiemer, D.F. Synthesis of Geometric Isoprenoid Bisphosphonate Isomers and Activity towards Protein Geranylgeranylation. Abstr. Pap. Am. Chem. Soc. 2007.

Wiemer, A.J., Tong, H., Wiemer, D.F., and Hohl, R.J. Geranyl and farnesyl bisphosphonates inhibit protein geranylgeranylation through GGPP depletion. 17th International Conference on Phosphorus Chemistry, Xiamen, China. 2007.

Wiemer, A.J., Vonnahme, L.J., and Hohl, R.J. Inhibition of geranylgeranyl pyrophosphate synthase results in altered small GTPase levels in multiple myeloma. Experimental Biology Annual Meeting, Washington, DC. 2007.

Wiemer, A.J., Kuder, C.H., Yu, J.S., Maalouf, M.A., Tong, H., Wiemer, D.F., and Hohl, R.J. Synthesis and biological activity of digeranyl bisphosphonate analogs. 41st Midwest Regional Meeting of the American Chemical Society, Quincy, IL. 2006.

Wiemer, A.J., Shull, L.W., Yu, J.S., Tong, H., Wiemer, D.F., and Hohl, R.J. Bisphosphonate-induced depletion of geranylgeranyl pyrophosphate alters processing of Ras superfamily GTPases. AACR 97th Annual Meeting, Washington, D.C. 2006.

Wiemer, A.J., Shull, L.W., Maalouf, M.A., Yu, J.S., Tong, H., Wiemer, D.F., and Hohl, R.J. Inhibition of Protein Geranylgeranylation with Isoprenoid Bisphosphonates. FASEB Summer Research Conference on Protein Lipidation, Signaling and Membrane Domain, Palm Desert, CA. 2006.

Wiemer, A.J., Neighbors, J.D., Hohl, R.J., and Wiemer, D.F. The schweinfurthin family of anti-proliferative agents: synthesis and biological activity of both enantiomers of 3-deoxyschweinfurthin B. 37th Great Lakes Regional Meeting of the American Chemical Society, Milwaukee, WI. 2006.

Lamb, K.M., Wiemer, A.J., Yu, J.S., Shull, L.W., Hohl, R.J., and Wiemer, D.F. Synthesis of pivaloyloxymethyl isoprenoid bisphosphonate prodrugs and effects on the biological activity. 41st Midwest Regional Meeting of the American Chemical Society, Quincy, IL. 2006.

Askeland, E.J., Wiemer, A.J., and Hohl, R.J. Synergism between anti-leukemia therapeutics and isoprenoid pathway inhibitors in K562 leukemia cells. Blood. 108: 288b-288b. 2006.

Yu, J.S., Wiemer, A.J., Hohl, R.J., and Wiemer, D.F. Synthesis and biological evaluation of all alpha-hydroxyfarnesylphosphonate geometric isomers on RAS farnesylation. Abstr. Pap. Am. Chem. Soc. 230: U2754-U2754. 2005.

Swanson, K.M., Tong, H., Wiemer, A.J., Murthy, S., and Hohl, R.J. Potential mechanisms for the anti-myeloma properties of bisphosphonates. J Clin Oncol. 23: 581s-581s. 2005.

Maalouf, M.A., Wiemer, A.J., Hohl, R.J., and Wiemer, D.F. Anthranilate based analogues of farnesyl pyrophosphate. Abstr. Pap. Am. Chem. Soc. 229: U191-U191. 2005.

Zehnder, D.W., Wiemer, A.J., Hohl, R.J., and Wiemer, D.F. Synthesis of PEG-modified derivatives of perillyl alcohol. Abstr. Pap. Am. Chem. Soc. 227: U189-U190. 2004.

Swanson, K.M., Wiemer, A.J., and Hohl, R.J. Bisphosphonates influence isoprenylation of small GTPases in human myeloma cells. Blood. 104: 928a-928a. 2004.

Shull, L.W., Wiemer, A.J., Hohl, R.J., and Wiemer, D.F. Impact of terpenoid bisphosphonates on isoprenoid metabolism. Abstr. Pap. Am. Chem. Soc. 228: U964-U964. 2004.

Maalouf, M.A., Wiemer, A.J., Hohl, R.J., and Wiemer, D.F. Synthesis and bioactivity of fluorescent analogues of farnesyl pyrophosphate. Abstr. Pap. Am. Chem. Soc. 2004.

Kim, M.K., Kleckley, T.S., Wiemer, A.J., Ownsby, S.E., Wiemer, D.F., and Hohl, R.J. Design and synthesis of fluorescent probes for protein prenylation. Abstr. Pap. Am. Chem. Soc. 224: U33-U33. 2002.

Chen, X.M., Wiemer, D.F., Wiemer, A.J., and Hohl, R.J. Synthesis and bioactivity of phosphonate analogs of cytosine arabinoside monophosphate. Abstr. Pap. Am. Chem. Soc. 224: U260-U261. 2002.

Kleckley, T.S., Wiemer, D.F., Ownby, S.E., Wiemer, A.J., and Hohl, R.J. Fluorescent probes of protein prenylation. Abstr. Pap. Am. Chem. Soc. 221: U53-U53. 2001.

Jung, K.Y., Chen, X.M., Wiemer, D.F., Wiemer, A.J., and Hohl, R.J. Phosphonate analogues of cytosine arabinoside monophosphate. 15th International Conference on Phosphorus Chemistry. 2001.

Wiemer, D.F., Jung, K.Y., Wiemer, A.J., Holstein, S.A., and Hohl, R.J. Ara-C Phosphonates: A Strategy for Treatment of Leukemias Resistant to Ara-C. Stohlman Symposium, The Leukemia and Lymphoma Society. 2000.