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Lipophilic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR Investigation
Open accessAbstract
Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.
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Citations
Cited by
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Oldfield, E., & Lin, F. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201103110 · Cited by 391
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Rodriguez, J. B., & Gallo‐Rodriguez, C. (2019) · ChemMedChem · doi:10.1002/cmdc.201800693 · Cited by 267
Targeting Small GTPases and Their Prenylation in Diabetes Mellitus
Gendaszewska-Darmach, E., Garstka, M. A., & Błażewska, K. M. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00410 · Cited by 35
Structural Insight into Geranylgeranyl Diphosphate Synthase (GGDPS) for Cancer Therapy
Pham, A. C., Holstein, S. A., & Borgstahl, G. E. O. (2024) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-23-0358 · Cited by 9
Metadata
- Authors
- Zhang, Y., Cao, R., Yin, F., Hudock, M. P., Guo, R.-T., Krysiak, K., Mukherjee, S., Gao, Y.-G., Robinson, H., Song, Y., No, J. H., Bergan, K., Leon, A., Cass, L., Goddard, A., Chang, T.-K., Lin, F.-Y., Beek, E. V., Papapoulos, S., Wang, A. H.-J., Kubo, T., Ochi, M., Mukkamala, D., & Oldfield, E.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2009-03-23
- Volume
- 131
- Issue
- 14
- Pages
- 5153-5162
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2171745736
- Cited by
- 178
- References
- 0
- FWCI
- 9.10
- Type
- journal article
- Language
- en
- Open access
- green
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- The paper
- Zhang, Y., Cao, R., Yin, F., Hudock, M. P., Guo, R.-T., Krysiak, K., Mukherjee, S., Gao, Y.-G., Robinson, H., Song, Y., No, J. H., Bergan, K., Leon, A., Cass, L., Goddard, A., Chang, T.-K., Lin, F.-Y., Beek, E. V., Papapoulos, S., . . . Oldfield, E. (2009). Lipophilic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR Investigation. Journal of the American Chemical Society. https://doi.org/10.1021/ja808285e
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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