Open AccessDiscovery of Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia
Author(s) -
Jing Liu,
Chao Yang,
Cathy A. Simpson,
Deborah DeRyckere,
Amy Van Deusen,
Michael J. Miley,
Dmitri Kireev,
Jacqueline Norris-Drouin,
Susan Sather,
Debra Hunter,
Victoria K. Korboukh,
H. S. Patel,
William P. Janzen,
Mischa Machius,
Gary L. Johnson,
H. Shelton Earp,
Douglas K. Graham,
Stephen V. Frye,
Xiaodong Wang
Publication year - 2012
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml200239k
Subject(s) - kinase , small molecule , lymphoblastic leukemia , leukemia , cancer research , ectopic expression , lead compound , pharmacology , chemistry , medicine , biochemistry , gene , immunology , in vitro
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.