Worry is the principle characteristic of generalised anxiety disorder, and has been linked to deficient attentional control, a main function of working memory (WM). Adaptive WM training and mindfulness meditation practice (MMP) have both shown potential to increase attentional control. The present study hence investigates the individual and combined effects of MMP and a dual adaptive n-back task on a non-clinical, randomised sample of high worriers. 60 participants were tested before and after seven days of training. Assessment included self-report questionnaires, as well as performance tasks measuring attentional control and working memory capacity. Combined training resulted in continued reduction in worry in the week after training, highlighting the potential of utilising n-back training as an adjunct to established clinical treatment. Engagement with WM training correlated with immediate improvements in attentional control and resilience, with worry decreasing over time. Implications of these findings and suggestions for future research are discussed.

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.

Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4-d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4-d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate.