Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways

Satish R. Malwal, Bing O'Dowd, Xinxin Feng, Petri Turhanen, Christopher Shin, Jiaqi Yao, Boo Kyung Kim, Noman Baig, Tianhui Zhou, Sandhya Bansal, Rahul L. Khade, Yong Zhang, Eric Oldfield

Research output: Contribution to journalArticle

Abstract

Bisphosphonates are a major class of drugs used to treat osteoporosis, Paget's disease, and cancer. They have been proposed to act by inhibiting one or more targets including protein prenylation, the epidermal growth factor receptor, or the adenine nucleotide translocase. Inhibition of the latter is due to formation in cells of analogs of ATP: the isopentenyl ester of ATP (ApppI) or an AppXp-type analog of ATP, such as AMP-clodronate (AppCCl2p). We screened both ApppI as well as AppCCl2p against a panel of 369 kinases finding potent inhibition of some tyrosine kinases by AppCCl2p, attributable to formation of a strong hydrogen bond between tyrosine and the terminal phosphonate. We then synthesized bisphosphonate preprodrugs that are converted in cells to other ATP-analogs, finding low nM kinase inhibitors that inhibited cell signaling pathways. These results help clarify our understanding of the mechanisms of action of bisphosphonates, potentially opening up new routes to the development of bone resorption, anticancer, and anti-inflammatory drug leads.

Original languageEnglish (US)
Pages (from-to)7568-7578
Number of pages11
JournalJournal of the American Chemical Society
Volume140
Issue number24
DOIs
StatePublished - Jun 20 2018

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Malwal, S. R., O'Dowd, B., Feng, X., Turhanen, P., Shin, C., Yao, J., Kim, B. K., Baig, N., Zhou, T., Bansal, S., Khade, R. L., Zhang, Y., & Oldfield, E. (2018). Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways. Journal of the American Chemical Society, 140(24), 7568-7578. https://doi.org/10.1021/jacs.8b02363