pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry.

BACKGROUND: AZD0156 and AZD6738 are potent and selective inhibitors of ataxia-telangiectasia-kinase (ATM) and ataxia-telangiectasia-mutated and Rad3-related (ATR), respectively, important sensors/signallers of DNA damage. METHODS: We used multiplexed targeted-mass-spectrometry to select pRAD50(Ser635) as a pharmacodynamic biomarker for AZD0156-mediated ATM inhibition from a panel of 45 peptides, then developed and tested a clinically applicable immunohistochemistry assay for pRAD50(Ser635) detection in FFPE tissue. RESULTS: We found moderate pRAD50 baseline levels across cancer indications. pRAD50 was detectable in 100% gastric cancers (n = 23), 99% colorectal cancers (n = 102), 95% triple-negative-breast cancers (TNBC) (n = 40) and 87.5% glioblastoma-multiformes (n = 16). We demonstrated AZD0156 target inhibition in TNBC patient-derived xenograft models; where AZD0156 monotherapy or post olaparib treatment, resulted in a 34-72% reduction in pRAD50. Similar inhibition of pRAD50 (68%) was observed following ATM inhibitor treatment post irinotecan in a colorectal cancer xenograft model. ATR inhibition, using AZD6738, increased pRAD50 in the ATM-proficient models whilst in ATM-deficient models the opposite was observed, suggesting pRAD50 pharmacodynamics post ATR inhibition may be ATM-dependent and could be useful to determine ATM functionality in patients treated with ATR inhibitors. CONCLUSION: Together these data support clinical utilisation of pRAD50 as a biomarker of AZD0156 and AZD6738 pharmacology to elucidate clinical pharmacokinetic/pharmacodynamic relationships, thereby informing recommended Phase 2 dose/schedule.

A questionnaire study to explore the views of people with multiple sclerosis of using smartphone technology for health care purposes.

PURPOSE: Delivering interventions over the lifetime of people with chronic conditions is an international healthcare challenge. The benefits of technology in healthcare have been demonstrated in many health conditions. This study aims to seek the views of People with multiple sclerosis (MS) of the feasibility and perceived acceptability of smartphone use for healthcare purposes. METHODS: Using SurveyMonkey™, respondents answered 21 items about their smartphone use and acceptance of smartphones in healthcare. Descriptive statistics were used to summarize data from closed questions. Content analysis was used for open questions. RESULTS: Most of the self-selected 197 respondents were female (138/197;70.1%), aged 42.78 ± 10.29 years, had relapsing-remitting MS (143/187;76.5%), and mobilized without an aid (154/197;78.17%). Most respondents reported having smartphone access (174/191;91.1%) and owning smartphones (167/192;86.97%). Perceived benefits of smartphones included improved healthcare access (119/190;62.63%) and greater independence (124/190;65.26%). The top three concerns included reduced contact with Healthcare Professionals (66/186;35.48%), data security (60/186;32.26%) and visual impairment (47/184;25.54%). CONCLUSION: These findings suggest that smartphone use is extensive, frequent, and acceptable for healthcare purposes in this self-selected sample. People with MS should be consulted during the design of smartphone-based interventions, as specific concerns were raised. Future studies should explore how this technology may be best used and implemented in practice. Implications for Rehabilitation Smartphones may have the potential to improve the implementation of best practice among people with multiple sclerosis (MS) This study found that smartphone use is widespread among people with MS, the majority of whom would accept using smartphones in healthcare. Some potential issues were raised, and would need to be considered during the development and implementation of smartphone-based interventions. Issues included potential lack of contact with health-care professionals, data security, and visual impairment.

Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point.

There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.