4C4H

Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1

Summary for 4C4H

• Entry DOI: 10.2210/pdb4c4h/pdb
• Related: 4C4E 4C4F 4C4G 4C4I 4C4J
• Descriptor: DUAL SPECIFICITY PROTEIN KINASE TTK, tert-butyl 6-((2-chloro-4-(dimethylcarbamoyl)phenyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate, 2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL, ... (4 entities in total)
• Functional Keywords: transferase, protein kinase, mitosis, structure-based design
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 36920.61

Authors

Naud, S.,Westwood, I.M.,Faisal, A.,Sheldrake, P.,Bavetsias, V.,Atrash, B.,Liu, M.,Hayes, A.,Schmitt, J.,Wood, A.,Choi, V.,Boxall, K.,Mak, G.,Gurden, M.,Valenti, M.,de Haven Brandon, A.,Henley, A.,Baker, R.,McAndrew, C.,Matijssen, B.,Burke, R.,Eccles, S.A.,Raynaud, F.I.,Linardopoulos, S.,van Montfort, R.,Blagg, J. (deposition date: 2013-09-05, release date: 2013-12-04, Last modification date: 2023-12-20)

Primary citation

Naud, S.,Westwood, I.M.,Faisal, A.,Sheldrake, P.W.,Bavetsias, V.,Atrash, B.,Cheung, K.J.,Liu, M.,Hayes, A.,Schmitt, J.,Wood, A.,Choi, V.,Boxall, K.,Mak, G.,Gurden, M.,Valenti, M.,De-Haven-Brandon, A.,Henley, A.,Baker, R.,Mcandrew, C.,Matijssen, B.,Burke, R.,Hoelder, S.,Eccles, S.A.,Raynaud, F.I.,Linardopoulos, S.,Van Montfort, R.L.M.,Blagg, J.
Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3, 2-C]Pyridine Inhibitors of the Mitotic Kinase Monopolar Spindle 1 (Mps1).
J.Med.Chem., 56:10045-, 2013

PubMed Abstract: The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.

PubMed: 24256217
DOI: 10.1021/JM401395S

Experimental method

X-RAY DIFFRACTION (2.8 Å)