5K0K

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC2434

Summary for 5K0K

• Entry DOI: 10.2210/pdb5k0k/pdb
• Related: 5K0X
• Descriptor: Tyrosine-protein kinase Mer, CHLORIDE ION, 15-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-4,5,6,7,9,10,11,12-octahydro-2,16-(azenometheno)pyrrolo[2,1-d][1,3,5,9]te traazacyclotetradecin-8(3H)-one, ... (5 entities in total)
• Functional Keywords: macrocyclic, pyrrolopyrimidines, drug design, fibrinolytic agents, protein kinase inhibitors, proto-oncogene proteins, pyrimidines, receptor protein-tyrosine kinases, structure-activity relationship, thrombosis, 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: 72939.09

Authors

Wang, X.,Liu, J.,Zhang, W.,Stashko, M.A.,Nichols, J.,DeRyckere, D.,Miley, M.J.,Norris-Drouin, J.,Chen, Z.,Machius, M.,Wood, E.,Graham, D.K.,Earp, H.S.,Graham, K.,Kireev, D.,Frye, S.V. (deposition date: 2016-05-17, release date: 2017-01-11, Last modification date: 2023-09-27)

Primary citation

Wang, X.,Liu, J.,Zhang, W.,Stashko, M.A.,Nichols, J.,Miley, M.J.,Norris-Drouin, J.,Chen, Z.,Machius, M.,DeRyckere, D.,Wood, E.,Graham, D.K.,Earp, H.S.,Kireev, D.,Frye, S.V.
Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors.
ACS Med Chem Lett, 7:1044-1049, 2016

PubMed Abstract: Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reducing cancer cell survival and redirecting the innate immune response. Recently, we have designed novel and potent macrocyclic pyrrolopyrimidines as MerTK inhibitors using a structure-based approach. The most active macrocycles had an EC below 40 nM in a cell-based MerTK phosphor-protein ELISA assay. The X-ray structure of macrocyclic analogue complexed with MerTK was also resolved and demonstrated macrocycles binding in the ATP binding pocket of the MerTK protein as anticipated. In addition, the lead compound (UNC3133) had a 1.6 h half-life and 16% oral bioavailability in a mouse PK study.

PubMed: 27994735
DOI: 10.1021/acsmedchemlett.6b00221

Experimental method

X-RAY DIFFRACTION (2.545 Å)