TY - JOUR
T1 - Design, synthesis, and functional evaluation of triazine-based bivalent agents that simultaneously target the active site and hot spot of phosphatase Cdc25B
AU - Nagaoka, Yosei
AU - Parvatkar, Prakash
AU - Hirai, Go
AU - Ohkanda, Junko
N1 - Funding Information:
This study was supported by the Japan Society for the Promotion of Science ( 21H02077 , 20H04769 , 20K21248 , 18H02106 ) and The Koyanagi Foundation (J.O.). Recombinant enzymes were provided by Dr. Toshiaki Miyazaki, Medical & Biological Laboratories, Co., Ltd. (Ina, Japan). We thank the Comprehensive Analysis Center of ISIR, Osaka University, and the Instrumental Center of Shinshu University, for assistance with mass analysis.
Funding Information:
This study was supported by the Japan Society for the Promotion of Science (21H02077, 20H04769, 20K21248, 18H02106) and The Koyanagi Foundation (J.O.). Recombinant enzymes were provided by Dr. Toshiaki Miyazaki, Medical & Biological Laboratories, Co. Ltd. (Ina, Japan). We thank the Comprehensive Analysis Center of ISIR, Osaka University, and the Instrumental Center of Shinshu University, for assistance with mass analysis.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/9/15
Y1 - 2021/9/15
N2 - Cdc25B phosphatase catalyzes the dephosphorylation and activation of cyclin-dependent kinases 2 (CDK2/CycA) and their overexpression has been reported in cancers. Although Cdc25B has received much attention as a drug target, its flat and featureless surface makes it challenging to develop new agents targeting this protein. In this study, we investigated the rational design of a series of bivalent triazine-based derivatives with the aim of simultaneously targeting the active site and the remote hotspot critical for the interaction with CDK2/CycA. Compounds 1e and 10, containing aromatic residues, were shown to inhibit Cdc25B activity selectively over Cdc25A at low micromolar concentration.
AB - Cdc25B phosphatase catalyzes the dephosphorylation and activation of cyclin-dependent kinases 2 (CDK2/CycA) and their overexpression has been reported in cancers. Although Cdc25B has received much attention as a drug target, its flat and featureless surface makes it challenging to develop new agents targeting this protein. In this study, we investigated the rational design of a series of bivalent triazine-based derivatives with the aim of simultaneously targeting the active site and the remote hotspot critical for the interaction with CDK2/CycA. Compounds 1e and 10, containing aromatic residues, were shown to inhibit Cdc25B activity selectively over Cdc25A at low micromolar concentration.
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U2 - 10.1016/j.bmcl.2021.128265
DO - 10.1016/j.bmcl.2021.128265
M3 - Article
C2 - 34273487
AN - SCOPUS:85110369784
SN - 0960-894X
VL - 48
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
M1 - 128265
ER -
