- Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways
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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.
- Malwal, Satish R.,O'Dowd, Bing,Feng, Xinxin,Turhanen, Petri,Shin, Christopher,Yao, Jiaqi,Kim, Boo Kyung,Baig, Noman,Zhou, Tianhui,Bansal, Sandhya,Khade, Rahul L.,Zhang, Yong,Oldfield, Eric
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supporting information
p. 7568 - 7578
(2018/05/31)
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- Formulation for treatment of osteoporosis
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The present invention provides pharmaceutical formulations comprising at least one bisphosphonate and an absorption enhancing agent essentially consisting of a medium chain glyceride or a mixture of medium chain glycerides. The said pharmaceutical formulations are useful for the inhibition of bone resorption and for the treatment and prevention of osteoporosis.
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- Regimen for treatment or prophylaxis of osteoporosis
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Methods for treating or preventing osteoporosis, including regimens for intermittent dosing of bone resorption inhibiting polyphosphonate compound or a pharmaceutically acceptable salt or ester of any such compound.
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