- Discovery of small molecule Mer kinase inhibitors for the treatment of pediatric acute lymphoblastic leukemia
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Ectopic Mer expression promotes pro-survival signaling and contributes to leukemogenesis and chemoresistance in childhood acute lymphoblastic leukemia (ALL). Consequently, Mer kinase inhibitors may promote leukemic cell death and further act as chemosensitizers increasing efficacy and reducing toxicities of current ALL regimens. We have applied a structure-based design approach to discover novel small molecule Mer kinase inhibitors. Several pyrazolopyrimidine derivatives effectively inhibit Mer kinase activity at subnanomolar concentrations. Furthermore, the lead compound shows a promising selectivity profile against a panel of 72 kinases and has excellent pharmacokinetic properties. We also describe the crystal structure of the complex between the lead compound and Mer, opening new opportunities for further optimization and new template design.
- Liu, Jing,Yang, Chao,Simpson, Catherine,Deryckere, Deborah,Van Deusen, Amy,Miley, Michael J.,Kireev, Dmitri,Norris-Drouin, Jacqueline,Sather, Susan,Hunter, Debra,Korboukh, Victoria K.,Patel, Hari S.,Janzen, William P.,MacHius, Mischa,Johnson, Gary L.,Earp, H. Shelton,Graham, Douglas K.,Frye, Stephen V.,Wang, Xiaodong
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p. 129 - 134
(2012/04/04)
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- Microwave-assisted, divergent solution-phase synthesis of 1,3,6-trisubstituted pyrazolo[3,4- d ]pyrimidines
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A concise and highly divergent synthetic route has been developed to rapidly access 1,3,6-trisubstituted pyrazolopyrimidines. The synthesis features a microwave assisted one-pot N1-alkylation/Suzuki-Miyaura reaction as the key step. The sequence of the synthetic scheme can be varied to selectively modify the N1, C3, or C6 position at a late synthetic stage, thereby providing a highly efficient approach to explore the structure-activity relationships of pyrazolopyrimidine derivatives. The scope of these reactions has also been explored.
- Liu, Jing,Wang, Xiaodong
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p. 414 - 420
(2011/08/22)
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- PYRAZOLOPYRIMIDINE COMPOUNDS FOR THE TREATMENT OF CANCER
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Compound of Formula (I): are described, along with pharmaceutically acceptable salts thereof, compositions containing the same, and methods of use thereof in the treatment of cancer.
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