Identification of the hot spot residues for pyridine derivative inhibitor CCT251455 and ATP substrate binding on monopolar spindle 1 (MPS1) kinase by molecular dynamic simulation

Article

作者: Duan, Wenxiu ; Han, Qianqian ; Wan, Jiajia ; Liu, Dan ; Hu, Shuangyun ; Chen, Kai ; Ge, Yushu ; Wu, Jiang ; Sun, Xuan ; Li, Wenqian

Protein kinase monopolar spindle 1 plays an important role in spindle assembly checkpoint at the onset of mitosis. Over expression of MPS1 correlated with a wide range of human tumors makes it an attractive target for finding an effective and specific inhibitor. In this work, we performed molecular dynamics simulations of protein MPS1 itself as well as protein bound systems with the inhibitor and natural substrate based on crystal structures. The reported orally bioavailable 1 h-pyrrolo [3,2-c] pyridine inhibitors of MPS1 maintained stable binding in the catalytic site, while natural substrate ATP could not stay. Comparative study of stability and flexibility of three systems reveals position shifting of β-sheet region within the catalytic site, which indicates inhibition mechanism was through stabilizing the β-sheet region. Binding free energies calculated with MM-GB/PBSA method shows different binding affinity for inhibitor and ATP. Finally, interactions between protein and inhibitor during molecular dynamic simulations were measured and counted. Residue Gly605 and Leu654 were suggested as important hot spots for stable binding of inhibitor by molecular dynamic simulation. Our results reveal an important position shifting within catalytic site for non-inhibited proteins. Together with hot spots found by molecular dynamic simulation, the results provide important information of inhibition mechanism and will be referenced for designing novel inhibitors.

2016-04-28·Journal of Medicinal Chemistry1区 · 医学

Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach

1区 · 医学

Article

作者: O'Fee, Lisa ; Solanki, Savade ; Eccles, Suzanne A. ; Schmitt, Jessica ; Valenti, Melanie ; Roberts, Jennie ; Matijssen, Berry ; Linardopoulos, Spiros ; Henley, Alan T. ; Naud, Sebastien ; Baker, Ross ; Westwood, Isaac M. ; Blagg, Julian ; De Haven Brandon, Alexis ; Saville, Harry ; Faisal, Amir ; Innocenti, Paolo ; Raynaud, Florence I. ; Box, Gary ; van Montfort, Rob L. M. ; Hayes, Angela ; Burke, Rosemary ; Hoelder, Swen ; Cronin, Nora ; Mak, Grace Wing-Yan ; Woodward, Hannah L.

Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.

2015-08-15·Cancer Research1区 · 医学

Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance

1区 · 医学

Article

作者: Cheung, Kwai-Ming J. ; McAndrew, Craig ; Westwood, Isaac M. ; Van Montfort, Rob L.M. ; Burke, Rosemary ; Workman, Paul ; Hoelder, Swen ; Mak, Grace ; Blagg, Julian ; Boxall, Kathy ; Naud, Sébastien ; Faisal, Amir ; Gurden, Mark D. ; Wood, Amy ; Schmitt, Jessica ; Linardopoulos, Spiros

AbstractAcquired resistance to therapy is perhaps the greatest challenge to effective clinical management of cancer. With several inhibitors of the mitotic checkpoint kinase MPS1 in preclinical development, we sought to investigate how resistance against these inhibitors may arise so that mitigation or bypass strategies could be addressed as early as possible. Toward this end, we modeled acquired resistance to the MPS1 inhibitors AZ3146, NMS-P715, and CCT251455, identifying five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed how the MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. Notably, we show that these mutations occur in nontreated cancer cell lines and primary tumor specimens, and that they also preexist in normal lymphoblast and breast tissues. In a parallel piece of work, we also show that the EGFR p.T790M mutation, the most common mutation conferring resistance to the EGFR inhibitor gefitinib, also preexists in cancer cells and normal tissue. Our results therefore suggest that mutations conferring resistance to targeted therapy occur naturally in normal and malignant cells and these mutations do not arise as a result of the increased mutagenic plasticity of cancer cells. Cancer Res; 75(16); 3340–54. ©2015 AACR.

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