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Discovery of Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia
| Content Provider | Semantic Scholar |
|---|---|
| Author | Liu, Jing Yang, Chao Simpson, Catherine DeRyckere, Deborah Deusen, Amy Lynnette Van Miley, Michael J. Kireev, Dmitri B. Norris-Drouin, Jacqueline L. Sather, Susan Louise Hunter, Debra M. Korboukh, Victoria K. Patel, Hari Shankar Janzen, William P. Machius, Mischa Johnson, Gary L. Earp, Henry Shelton Graham, Douglas Kim Frye, Stephen V. Wang, Xiaodong |
| Copyright Year | 2012 |
| Abstract | 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. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.mch.estranky.sk/file/119/2012acs-mchl-3-129-34-mertyro3tki_pdb3tcp-wang-_semkf.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
