Development of Potent Pyrazolopyrimidinone-Based WEE1 Inhibitors with Limited Single-Agent Cytotoxicity for Cancer Therapy.
Development of Potent Pyrazolopyrimidinone-Based WEE1 Inhibitors with Limited Single-Agent Cytotoxicity for Cancer Therapy.
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DOI：
10.1002/cmdc.201800188
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发表时间：
2018-08-20
期刊：
影响因子：
3.4
通讯作者：
Reigan P
中科院分区：
文献类型：
--
作者：
Matheson CJ;Casalvieri KA;Backos DS;Reigan P
WEE1 kinase regulates the G2-M cell-cycle checkpoint, a critical mechanism for DNA repair in cancer cells that can confer resistance to DNA-damaging agents. We previously reported a series of pyrazolopyrimidinones based on AZD1775, a known WEE1 inhibitor, as an initial investigation into the structural requirements for WEE1 inhibition. Our lead inhibitor demonstrated WEE1 inhibition in the same nanomolar range as AZD1775, and potentiated the effects of cisplatin in medulloblastoma cells, but had reduced single-agent cytotoxicity. These results prompted the development of a more comprehensive series of WEE1 inhibitors. Here, we report a series of pyrazolopyrimidinones and identify a more potent WEE1 inhibitor than AZD1775 and additional compounds that demonstrate that WEE1 inhibition can be achieved with reduced single-agent cytotoxicity. These studies support that WEE1 inhibition can be uncoupled from the potent cytotoxic effects observed with AZD1775, and this may have important ramifications in the clinical setting where WEE1 inhibitors are used as chemosensitizers for DNA-targeted chemotherapy. The activity of WEE1 kinase is critical for DNA repair in cancer cells and can confer resistance to DNA-targeted agents. Here, we report that structural modifications to the WEE1 inhibitor AZD1775 can result in improved inhibitory potency against WEE1 kinase activity with limited cytotoxicity. These studies may have important implications in the clinical setting where WEE1 inhibitors are used as chemosensitizers for DNA-targeted chemotherapy.
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DOI：
10.1083/jcb.200905059
发表时间：
2010-03-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Beck H;Nähse V;Larsen MS;Groth P;Clancy T;Lees M;Jørgensen M;Helleday T;Syljuåsen RG;Sørensen CS
通讯作者：
Sørensen CS
影响因子：
3.9
作者：
Music, Darija;Dahlrot, Rikke Hedegaard;Kristensen, Bjarne Winther
通讯作者：
Kristensen, Bjarne Winther
影响因子：
3.6
作者：
Brosse, N;Pinto, MF;Jamart-Grégoire, B
通讯作者：
Jamart-Grégoire, B
影响因子：
4
作者：
Matheson, Christopher J.;Venkataraman, Sujatha;Reigan, Philip
通讯作者：
Reigan, Philip
影响因子：
4.7
作者：
Slipicevic, Ana;Holth, Arild;Florenes, Vivi Ann
通讯作者：
Florenes, Vivi Ann