Innocenti, P., Woodward, H. L., Solanki, S., Naud, S., Westwood, I. M., Cronin, N., Hayes, A., Roberts, J., Henley, A. T., Baker, R., Faisal, A., Mak, G. W. Y., Box, G., Valenti, M., Brandon, A. D. H., O'Fee, L., Saville, H., Schmitt, J., Matijssen, B., Burke, R., van Montfort, R. L. M., Raynaud, F. I., Eccles, S. A., Linardopoulos, S., Blagg, J., Hoelder, S. (2016) Rapid Discovery of Pyrido 3,4-d pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach. JOURNAL OF MEDICINAL CHEMISTRY, 59 (8). pp. 3671-3688. ISSN 0022-2623

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Abstract

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.

Item Type:	Article
Authors (ICR Faculty only):	hoelder, swen and Raynaud, Florence and Blagg, Julian and Eccles, Sue and Linardopoulos, Spiros and Van Montfort, Rob
All Authors:	Innocenti, P., Woodward, H. L., Solanki, S., Naud, S., Westwood, I. M., Cronin, N., Hayes, A., Roberts, J., Henley, A. T., Baker, R., Faisal, A., Mak, G. W. Y., Box, G., Valenti, M., Brandon, A. D. H., O'Fee, L., Saville, H., Schmitt, J., Matijssen, B., Burke, R., van Montfort, R. L. M., Raynaud, F. I., Eccles, S. A., Linardopoulos, S., Blagg, J., Hoelder, S.
Additional Information:	ISI Document Delivery No.: DL3FP Times Cited: 0 Cited Reference Count: 57 Innocenti, Paolo Woodward, Hannah L. Solanki, Savade Naud, Sebastien Westwood, Isaac M. Cronin, Nora Hayes, Angela Roberts, Jennie Henley, Alan T. Baker, Ross Faisal, Amir Mak, Grace Wing-Yan Box, Gary Valenti, Melanie Brandon, Alexis De Haven O'Fee, Lisa Saville, Harry Schmitt, Jessica Matijssen, Berry Burke, Rosemary van Montfort, Rob L. M. Raynaud, Florence I. Eccles, Suzanne A. Linardopoulos, Spiros Blagg, Julian Hoelder, Swen Cancer Research U.K. [C309/A11566]; Cancer Research Technology Pioneer Fund; Sixth Element Capital; NHS; Breakthrough Breast Cancer (Breast Cancer Campaign forming Breast Cancer Now) This work was supported by Cancer Research U.K. [grant number C309/A11566]. We also acknowledge the Cancer Research Technology Pioneer Fund and Sixth Element Capital for funding (to P.I.) and NHS funding to the NIHR Biomedical Research Centre. S.L. is also supported by Breakthrough Breast Cancer (recently merged with Breast Cancer Campaign forming Breast Cancer Now). We thank the staff of DIAMOND Light Source for their support during data collection. We thank Dr. Amin Mirza, Dr. Maggie Liu, and Mr. Meirion Richards for their help with LC, NMR, and mass spectrometry. 0 AMER CHEMICAL SOC WASHINGTON J MED CHEM
Uncontrolled Keywords:	SMALL-MOLECULE INHIBITOR BREAST-CANCER CELLS MITOTIC CHECKPOINT CHROMOSOMAL INSTABILITY ASSEMBLY CHECKPOINT TTK INHIBITORS PROTEIN-KINASE EXPRESSION MITOSIS POTENT
Research teams:	ICR divisions > Breast Cancer Research > Drug Target Discovery ICR divisions > Cancer Therapeutics > Drug Target Discovery ICR divisions > Cancer Therapeutics > Tumour Biology & Metastasis ICR divisions > Breast Cancer Research > Target Discovery & Apoptosis ICR divisions > Cancer Therapeutics > Target Discovery & Apoptosis ICR divisions > Cancer Therapeutics > Medicinal Chemistry 1 (including Analytical Chemistry and In Silico Chemistry) ICR divisions > Cancer Therapeutics > Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) ICR divisions > Cancer Therapeutics > Hit Discovery & Structural Design ICR divisions > Structural Biology > Hit Discovery & Structural Design ICR divisions > Cancer Therapeutics > Medicinal Chemistry 4 ICR divisions > Cancer Therapeutics > Structure-Based Drug Design ICR divisions > Structural Biology > Structure-Based Drug Design
Depositing User:	Barry Jenkins
Date Deposited:	03 Jun 2016 14:31
Last Modified:	03 Jun 2016 14:36
URI:	http://publications.icr.ac.uk/id/eprint/15060

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