期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 8, 页码 3671-3688出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01811
关键词
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资金
- 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)
- Cancer Research UK [11566] Funding Source: researchfish
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.
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