6MEP

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC3437

Summary for 6MEP

• Entry DOI: 10.2210/pdb6mep/pdb
• Descriptor: Tyrosine-protein kinase Mer, CHLORIDE ION, cis-4-[(2-[(4-{[4-(1,3-dioxolan-2-yl)pyridin-2-yl]ethynyl}phenyl)amino]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}pyrimidin-4-yl)amino]cyclohexan-1-ol, ... (5 entities in total)
• Functional Keywords: macrocyclic, drug design, fibrinolytic agents, humans, models, molecular, 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)
• Total number of polymer chains: 2
• Total formula weight: 73272.02

Authors

Da, C.,Zhang, D.,Stashko, M.A.,Cheng, A.,Hunter, D.,Norris-Drouin, J.,Graves, L.,Machius, M.,Miley, M.J.,DeRyckere, D.,Earp, H.S.,Graham, D.K.,Frye, S.V.,Wang, X.,Kireev, D. (deposition date: 2018-09-06, release date: 2019-09-11, Last modification date: 2024-03-13)

Primary citation

Da, C.,Zhang, D.,Stashko, M.,Vasileiadi, E.,Parker, R.E.,Minson, K.A.,Huey, M.G.,Huelse, J.M.,Hunter, D.,Gilbert, T.S.K.,Norris-Drouin, J.,Miley, M.,Herring, L.E.,Graves, L.M.,DeRyckere, D.,Earp, H.S.,Graham, D.K.,Frye, S.V.,Wang, X.,Kireev, D.
Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology.
J.Am.Chem.Soc., 141:15700-15709, 2019

PubMed Abstract: Controlling which particular members of a large protein family are targeted by a drug is key to achieving a desired therapeutic response. In this study, we report a rational data-driven strategy for achieving restricted polypharmacology in the design of antitumor agents selectively targeting the TYRO3, AXL, and MERTK (TAM) family tyrosine kinases. Our computational approach, based on the concept of fragments in structural environments (FRASE), distills relevant chemical information from structural and chemogenomic databases to assemble a three-dimensional inhibitor structure directly in the protein pocket. Target engagement by the inhibitors designed led to disruption of oncogenic phenotypes as demonstrated in enzymatic assays and in a panel of cancer cell lines, including acute lymphoblastic and myeloid leukemia (ALL/AML) and nonsmall cell lung cancer (NSCLC). Structural rationale underlying the approach was corroborated by X-ray crystallography. The lead compound demonstrated potent target inhibition in a pharmacodynamic study in leukemic mice.

PubMed: 31497954
DOI: 10.1021/jacs.9b08660

Experimental method

X-RAY DIFFRACTION (2.893 Å)