4M3Q

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1917

Summary for 4M3Q

• Entry DOI: 10.2210/pdb4m3q/pdb
• Related: 2BRB 2POC 3BPR 3TCP
• Descriptor: Tyrosine-protein kinase Mer, CHLORIDE ION, MAGNESIUM 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: 72734.25

Authors

Zhang, W.,Zhang, D.,Stashko, M.A.,DeRyckere, D.,Hunter, D.,Kireev, D.B.,Miley, M.,Cummings, C.,Lee, M.,Norris-Drouin, J.,Stewart, W.M.,Sather, S.,Zhou, Y.,Kirkpatrick, G.,Machius, M.,Janzen, W.P.,Earp, H.S.,Graham, D.K.,Frye, S.,Wang, X. (deposition date: 2013-08-06, release date: 2013-11-27, Last modification date: 2023-09-20)

Primary citation

Zhang, W.,Zhang, D.,Stashko, M.A.,Deryckere, D.,Hunter, D.,Kireev, D.,Miley, M.J.,Cummings, C.,Lee, M.,Norris-Drouin, J.,Stewart, W.M.,Sather, S.,Zhou, Y.,Kirkpatrick, G.,Machius, M.,Janzen, W.P.,Earp, H.S.,Graham, D.K.,Frye, S.V.,Wang, X.
Pseudo-Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase Inhibitors.
J.Med.Chem., 56:9683-9692, 2013

PubMed Abstract: Abnormal activation or overexpression of Mer receptor tyrosine kinase has been implicated in survival signaling and chemoresistance in many human cancers. Consequently, Mer is a promising novel cancer therapeutic target. A structure-based drug design approach using a pseudo-ring replacement strategy was developed and validated to discover a new family of pyridinepyrimidine analogues as potent Mer inhibitors. Through SAR studies, 10 (UNC2250) was identified as the lead compound for further investigation based on high selectivity against other kinases and good pharmacokinetic properties. When applied to live cells, 10 inhibited steady-state phosphorylation of endogenous Mer with an IC50 of 9.8 nM and blocked ligand-stimulated activation of a chimeric EGFR-Mer protein. Treatment with 10 also resulted in decreased colony-forming potential in rhabdoid and NSCLC tumor cells, thereby demonstrating functional antitumor activity. The results provide a rationale for further investigation of this compound for therapeutic application in patients with cancer.

PubMed: 24195762
DOI: 10.1021/jm401387j

Experimental method

X-RAY DIFFRACTION (2.718 Å)