4MHA

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1817

Summary for 4MHA

• Entry DOI: 10.2210/pdb4mha/pdb
• Related: 2BRB 2POC 3BPR 3TCP 4M3Q 4MH7
• Descriptor: Tyrosine-protein kinase Mer, CHLORIDE ION, 2-(butylamino)-4-[(trans-4-hydroxycyclohexyl)amino]-N-(4-sulfamoylbenzyl)pyrimidine-5-carboxamide, ... (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: 72969.07

Authors

Zhang, W.,Mciver, A.,Stashko, M.A.,Deryckere, D.,Branchford, B.R.,Hunter, D.,Kireev, D.B.,Miley, D.B.M.,Norris-Drouin, J.,Stewart, W.M.,Lee, M.,Sather, S.,Zhou, Y.,Dipaola, J.A.,Machius, M.,Janzen, W.P.,Earp, H.S.,Graham, D.K.,Frye, S.,Wang, X. (deposition date: 2013-08-29, release date: 2014-05-21, Last modification date: 2023-09-20)

Primary citation

Zhang, W.,McIver, A.L.,Stashko, M.A.,DeRyckere, D.,Branchford, B.R.,Hunter, D.,Kireev, D.,Miley, M.J.,Norris-Drouin, J.,Stewart, W.M.,Lee, M.,Sather, S.,Zhou, Y.,Di Paola, J.A.,Machius, M.,Janzen, W.P.,Earp, H.S.,Graham, D.K.,Frye, S.V.,Wang, X.
Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis.
J.Med.Chem., 56:9693-9700, 2013

PubMed Abstract: The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo ring replacement strategy. The cocrystal structure of Mer with two compounds (7 and 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.

PubMed: 24219778
DOI: 10.1021/jm4013888

Experimental method

X-RAY DIFFRACTION (2.59 Å)