7LQD

Structure of Human MPS1 (TTK) covalently bound to RMS-07 inhibitor

7LQD の概要

• エントリーDOI: 10.2210/pdb7lqd/pdb
• 分子名称: Dual specificity protein kinase TTK or monopolar spindle 1 kinase, ~{N}-(2,6-diethylphenyl)-2-[[4-(4-methylpiperazin-1-yl)-2-(propanoylamino)phenyl]amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: protein kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37346.69

構造登録者

Santiago, A.S.,dos Reis, C.V.,Serafim, R.A.M.,Massirer, K.B.,Arruda, P.,Edwards, A.M.,Counago, R.M.,Structural Genomics Consortium (SGC) (登録日: 2021-02-13, 公開日: 2022-02-16, 最終更新日: 2024-10-23)

主引用文献

M Serafim, R.A.,da Silva Santiago, A.,Schwalm, M.P.,Hu, Z.,Dos Reis, C.V.,Takarada, J.E.,Mezzomo, P.,Massirer, K.B.,Kudolo, M.,Gerstenecker, S.,Chaikuad, A.,Zender, L.,Knapp, S.,Laufer, S.,Counago, R.M.,Gehringer, M.
Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor.
J.Med.Chem., 65:3173-3192, 2022

PubMed Abstract: Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer. While long drug-target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors have been reported. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor, , targeting a poorly conserved cysteine in the kinase's hinge region. shows potent MPS1 inhibitory activity and selectivity against all protein kinases with an equivalent cysteine but also in a broader kinase panel. We demonstrate potent cellular target engagement and pronounced activity against various cancer cell lines. The covalent binding mode was validated by mass spectrometry and an X-ray crystal structure. This proof of MPS1 covalent ligandability may open new avenues for the design of MPS1-specific chemical probes or drugs.

PubMed: 35167750
DOI: 10.1021/acs.jmedchem.1c01165

実験手法

X-RAY DIFFRACTION (1.95 Å)