2. Academic Validation
  3. Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia

Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia

  • ACS Med Chem Lett. 2012 Feb 9;3(2):129-134. doi: 10.1021/ml200239k.
Jing Liu 1,  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
Affiliations

Affiliation

  • 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
PMID: 22662287 DOI: 10.1021/ml200239k
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 sub-nanomolar 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.

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