3TCP

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC569

Summary for 3TCP

• Entry DOI: 10.2210/pdb3tcp/pdb
• Related: 2BRB 2POC 3BPR
• Descriptor: Tyrosine-protein kinase Mer, 1-[(trans-4-aminocyclohexyl)methyl]-N-butyl-3-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: tyrosine kinase, acute lymphoblastic leukemia, rational structure-based drug design, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane ; Single-pass type I membrane protein : Q12866
• Total number of polymer chains: 2
• Total formula weight: 72798.47

Authors

Liu, J.,Yang, C.,Simpson, C.,DeRyckere, D.,Van Deusen, A.,Miley, M.,Kireev, D.B.,Norris-Drouin, J.,Sather, S.,Hunter, D.,Patel, H.S.,Janzen, W.P.,Machius, M.,Johnson, G.,Earp, H.S.,Graham, D.K.,Frye, S.,Wang, X. (deposition date: 2011-08-09, release date: 2012-06-20, Last modification date: 2023-09-13)

Primary citation

Liu, J.,Yang, C.,Simpson, C.,Deryckere, D.,Van Deusen, A.,Miley, M.J.,Kireev, D.,Norris-Drouin, J.,Sather, S.,Hunter, D.,Korboukh, V.K.,Patel, H.S.,Janzen, W.P.,Machius, M.,Johnson, G.L.,Earp, H.S.,Graham, D.K.,Frye, S.V.,Wang, X.
Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia.
ACS Med Chem Lett, 3:129-134, 2012

PubMed 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.

PubMed: 22662287

Experimental method

X-RAY DIFFRACTION (2.69 Å)