Discovery of small molecule Mer kinase inhibitors for the treatment of pediatric acute lymphoblastic leukemia

Jing Liu, Chao Yang, Catherine Simpson, Deborah Deryckere, Amy Van Deusen, Michael J. Miley, Dmitri Kireev, Jacqueline Norris-Drouin, Susan Sather, Debra Hunter, Victoria K. Korboukh, Hari S. Patel, William P. Janzen, Mischa MacHius, Gary L. Johnson, H. Shelton Earp, Douglas K. Graham, Stephen V. Frye, Xiaodong Wang

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

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.

Original languageEnglish
Pages (from-to)129-134
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume3
Issue number2
DOIs
StatePublished - 9 Feb 2012
Externally publishedYes

Keywords

  • Mer inhibitors
  • acute lymphoblastic leukemia
  • chemosensitizer
  • pyrazolopyrimidines

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