Discovery of Pyridopyrimidinones that Selectively Inhibit the H1047R PI3Kα Mutant Protein.

The H1047R mutation of PIK3CA is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3KαH1047R over PI3KαWT is crucial due to the role that PI3KαWT plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3KαH1047R-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3KαH1047R with high selectivity over PI3KαWT, resulting in the discovery of compound 17. When dosed in the HCC1954 tumor model in mice, 17 provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3Kα inhibitors were obtained, revealing three distinct binding modes within PI3KαH1047R including a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047.

The role and scope of contemporary midwifery practice in Australia: A scoping review of the literature.

PROBLEM: Little is known about the breadth of midwifery scope within Australia, and few midwives work to their full scope of practice. BACKGROUND: Midwives in Australia are educated and professionally accountable to work in partnership with childbearing women and their families, yet they are currently hindered from practicing within their full scope of practice by contextual influences. AIMS: To perform a scoping review of the literature to map out the role and scope of contemporary midwifery practice in Australia To identify any key issues that impact upon working within the full scope of midwifery practice in the Australian context METHODS: A scoping review of the literature guided by the Arksey and O'Malley's five-stage methodological framework, and the 'best fit' framework synthesis using the Nursing and Midwifery Board of Australia's Midwifery Standards for Practice. FINDINGS: Key themes that emerged from the review included Partnership with women; The professional role of the midwife; and Contextual influences upon midwifery practice. DISCUSSION: Tensions were identified between the midwifery scope of practice associated with optimal outcomes for women and babies supported by current evidence and the actual role and scope of most midwives employed in models of care in the current Australian public healthcare system. CONCLUSIONS: There is a mismatch between the operational parameters for midwifery practice in Australia and the evidence-based models of continuity of midwifery carer that are associated with optimal outcomes for childbearing women and babies and the midwives themselves.