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

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MPS1 MC4 final.docx (2.63 MB)

Embargo End Date

ICR Authors

Burke, Rosemary
 Van Montfort, Robert
 Raynaud, Florence
 Linardopoulos, Spyridon
 Hoelder, Swen

Authors

Innocenti, P
Woodward, HL
Solanki, S
Naud, S
Westwood, IM
Cronin, N
Hayes, A
Roberts, J
Henley, AT
Baker, R
Faisal, A
Mak, GW-Y
Box, G
Valenti, M
De Haven Brandon, A
O'Fee, L
Saville, H
Schmitt, J
Matijssen, B
Burke, R
van Montfort, RLM
Raynaud, FI
Eccles, SA
Linardopoulos, S
Blagg, J
Hoelder, S

Document Type

Journal Article

Date

2016-04-28

Date Accepted

2016-03-01

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.

Citation

Journal of medicinal chemistry, 2016, 59 (8), pp. 3671 - 3688

DOI

10.1021/acs.jmedchem.5b01811

URI

https://repository.icr.ac.uk/handle/internal/233

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

AMER CHEMICAL SOC

ISSN

0022-2623

eISSN

1520-4804

Collections

Breast Cancer Research
Cancer Therapeutics
Structural Biology

Research Team

Drug Target Discovery
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Medicinal Chemistry 4 (including Analytical Chemistry)
Hit Discovery & Structural Design

Notes