A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.

There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT pathway discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a type 1 binding mode involving insertion of the CDK8 C terminus into the ligand binding site. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogs alter WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, we find that phosphorylation of STAT1(SER727) is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors

Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen.

WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target

Clinical Information Systems – Seen through the Ethics Lens

Objective: The more people there are who use clinical information systems (CIS) beyond their traditional intramural confines, the more promising the benefits are, and the more daunting the risks will be. This review thus explores the areas of ethical debates prompted by CIS conceptualized as smart systems reaching out to patients and citizens. Furthermore, it investigates the ethical competencies and education needed to use these systems appropriately. Methods: A literature review covering ethics topics in combination with clinical and health information systems, clinical decision support, health information exchange, and various mobile devices and media was performed searching the MEDLINE database for articles from 2016 to 2019 with a focus on 2018 and 2019. A second search combined these keywords with education. Results: By far, most of the discourses were dominated by privacy, confidentiality, and informed consent issues. Intertwined with confidentiality and clear boundaries, the provider-patient relationship has gained much attention. The opacity of algorithms and the lack of explicability of the results pose a further challenge. The necessity of sociotechnical ethics education was underpinned in many studies including advocating education for providers and patients alike. However, only a few publications expanded on ethical competencies. In the publications found, empirical research designs were employed to capture the stakeholders’ attitudes, but not to evaluate specific implementations. Conclusion: Despite the broad discourses, ethical values have not yet found their firm place in empirically rigorous health technology evaluation studies. Similarly, sociotechnical ethics competencies obviously need detailed specifications. These two gaps set the stage for further research at the junction of clinical information systems and ethics