PDB 3TCP deposited: 2011-08-09 modified: 2012-06-20
Title Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC569
Authors Deryckere, D., Earp, H.S., Frye, S.V., Graham, D.K., Hunter, D., Janzen, W.P., Johnson, G.L., Kireev, D., Korboukh, V.K., Liu, J., Machius, M., Miley, M.J., Norris-Drouin, J., Patel, H.S., Sather, S., Simpson, C., Van Deusen, A., Wang, X., Yang, C.
Structure factors resolution 2.69 rfactor 0.225 rfree 0.298
DPI 0.92 theoretical min: 0.50

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.

ACS Med Chem Lett 2012 Feb; 3(2):129-134 doi:

Cross References
Database source Identifier Description
PubMed 22662287
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3TCP/1 3TCP 1 monomer 0 1 4 1900
3TCP/2 3TCP 2 monomer 0 1 4 1842