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 tumours with chromosomal instability and aneuploidy; PTEN-deficient breast tumour cells are particularly dependent upon MPS1 for their survival making it a target of significant interest in oncology. In this talk I will present 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. Our research yielded the potent and selective chemical tool compound CCT251455, which stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP- and substrate peptide-binding. CCT251455 displays a favorable oral pharmacokinetic profile and shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model. It is therefore an attractive tool compound to further elucidate the therapeutic potential of MPS1 inhibition.
Discovery of Potent and Selective Inhibitors of Monopolar Spindle 1 (MPS1) Kinase
Video May 22, 2015
Behind the Science, S2 Ep 10: Kari Organtini on options for analyzing pesticides with GC-MS/MSVideo
Senior scientist Kari Organtini shows Jen Fournier an increasingly popular technology that uses GC-MS/MS at atmospheric pressure - or APGC - and is available as a simple source change for a triple quadrupole mass spectrometer so the MS can be used with either GC or LC.WATCH NOW