TY - JOUR
T1 - Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways
AU - Malwal, Satish R.
AU - O'Dowd, Bing
AU - Feng, Xinxin
AU - Turhanen, Petri
AU - Shin, Christopher
AU - Yao, Jiaqi
AU - Kim, Boo Kyung
AU - Baig, Noman
AU - Zhou, Tianhui
AU - Bansal, Sandhya
AU - Khade, Rahul L.
AU - Zhang, Yong
AU - Oldfield, Eric
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/6/20
Y1 - 2018/6/20
N2 - 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.
AB - 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.
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U2 - 10.1021/jacs.8b02363
DO - 10.1021/jacs.8b02363
M3 - Article
C2 - 29787268
AN - SCOPUS:85047559912
SN - 0002-7863
VL - 140
SP - 7568
EP - 7578
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 24
ER -