Discovery of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as PI3Kß/δ inhibitors for the treatment of PTEN-deficient tumours.

Starting from TGX-221, we designed a series of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as potent and selective PI3Kß/δ inhibitors. Structure-activity relationships and structure-property relationships around the aniline and the amide substituents are discussed. We identified compounds 17 and 18, which showed profound pharmacodynamic modulation of phosphorylated Akt in the PC3 prostate tumour xenograft, after a single oral dose. Compound 17 also gave significant inhibition of tumour growth in the PC3 prostate tumour xenograft model after chronic oral dosing.

A qualitative process evaluation of electronic session-by-session outcome measurement in child and adolescent mental health services.

BACKGROUND: Regular monitoring of patient progress is important to assess the clinical effectiveness of an intervention. Recently, initiatives within UK child and adolescent mental health services (CAMHS) have advocated the use of session-by-session monitoring to continually evaluate the patient's outcome throughout the course of the intervention. However, the feasibility and acceptability of such regular monitoring is unknown. METHOD: Semi-structured qualitative interviews were conducted with clinicians (n = 10), administrative staff (n = 8) and families (n = 15) who participated in a feasibility study of an electronic session-by-session outcome monitoring tool, (SxS), which is based on the Strengths and Difficulties Questionnaire (SDQ). This study took place in three CAMHS clinics in Nottinghamshire. The interview transcripts were thematically analysed. RESULTS: We found clinicians accepted the need to complete outcome measures, particularly valuing those completed by the patient. However, there were some difficulties with engaging clinicians in this practice and in the training offered. Generally, patients were supportive of completing SxS in the waiting room prior to the clinic session and assistance with the process from administrative staff was seen to be a key factor. Clinicians and families found the feedback reports created from SxS to be helpful for tracking progress, facilitating communication and engagement, and as a point of reflection. The use of technology was considered positively, although some technological difficulties hindered the completion of SxS. Clinicians and families appreciated the brevity of SxS, but some were concerned that a short questionnaire could not adequately encapsulate the complexity of the patient's issues. CONCLUSIONS: The findings show the need for appropriate infrastructure, mandatory training, and support to enable an effective system of session-by-session monitoring. Our findings indicate that clinicians, administrative staff and young people and their parents/carers would support regular monitoring if the system is easy to implement, with a standard 'clinic-wide' adoption of the procedure, and the resulting data are clinically useful.

Implementation of routine screening for Lynch syndrome in university and safety-net health system settings: successes and challenges.

PURPOSE: Routine screening for evidence of DNA mismatch repair abnormalities can identify colorectal cancer patients with Lynch syndrome, but impact in usual care settings requires study. After implementing routine screening at our university and safety-net health systems as usual practice, our aims were to determine outcomes, including screening process quality. METHODS: We conducted a retrospective cohort study from 1 May 2010 to 1 May 2011. Screening included reflexive immunohistochemistry to evaluate DNA mismatch repair protein expression for patients with colorectal cancer aged ≤70 years, with a cancer genetics team following up results. Screening outcomes, as well as challenges to a high-quality screening process were evaluated. RESULTS: We included 129 patients (mean age 56 years, 36% female); 100 had immunohistochemistry screening completed. Twelve patients had abnormal immunohistochemistry: four with definite Lynch syndrome, four with probable Lynch syndrome, and three without Lynch syndrome; one patient had an incomplete work-up. Lynch syndrome was confirmed for 6/13 asymptomatic relatives tested. Screening process quality was optimal for 77.5% of patients. Barriers to optimal quality screening included ensuring reflexive immunohistochemistry completion, complete follow-up of abnormal immunohistochemistry, and timely incorporation of results into clinical decision making. CONCLUSION: Usual care implementation of routine screening for Lynch syndrome can result in significant rates of detection, even in a largely safety-net setting. To optimize implementation, challenges to high-quality Lynch syndrome screening, such as ensuring reflexive screening completion and clinically indicated genetic testing and follow-up for abnormal screens, must be identified and addressed.

Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014.

The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC(50), led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21).

Implementing routine outcome measures in child and adolescent mental health services: from present to future practice.

BACKGROUND: Routine outcome measurement (ROM) in CAMHS is supported by U.K. Government policy. However, little is known about how measures are used in practice. METHOD: Data describing use of ROM, knowledge and attitudes regarding implementation were collected using a regional case-note audit, online survey and stakeholder workshop. RESULTS: While the principle of ROM was supported by stakeholders, baseline and follow-up outcome measurement occurred in less than a fifth of cases. Barriers to implementation included lack of training and resources, clinicians' perceptions of the limitations of existing measures and lack of regular feedback of outcome data. CONCLUSIONS: Implementation of ROM may be facilitated by session-by-session measures with immediate feedback to clinicians and patients.

Caregiver Perspectives on a Child's Diagnosis of 3q29 Deletion: "We Can't Just Wish This Thing Away".

OBJECTIVE: Genetic diagnoses are increasingly common in cases of intellectual disability and developmental delay. Although ascertainment of a relatively common, well-studied variant may provide guidance related to treatments and developmental expectations, it is less clear how the diagnosis of a rare variant affects caregivers, especially when the phenotype may include later-onset manifestations such as psychosis. In this study, we sought to identify caregiver concerns in the first qualitative study to assess the psychosocial impact of diagnosis on caregivers of individuals with 3q29 deletion syndrome (3q29Del), which is associated with a 40-fold increase in risk for psychosis. METHODS: Participants were recruited from the national 3q29Del registry housed at Emory University (3q29deletion.org). Fifteen participants completed a semistructured phone interview during which they were asked about their experiences before, during, and after their child received a diagnosis of 3q29Del. Interview responses were analyzed using the general inductive approach, and overarching themes were identified. RESULTS: We identified the following overarching themes: difficult "diagnostic odyssey," mixed feelings about diagnosis, frustration with degree of uncertainty, and importance of resources. Importantly, our data suggest that future risk for psychosis is often not disclosed by medical professionals, consistent with the experience of individuals with 22q11.2 deletion syndrome. CONCLUSIONS: These results highlight potential gaps in how caregivers are informed of risk for adult-onset conditions and indicate key caregiver concerns for consideration in the diagnosis of 3q29Del.

Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2-(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF-1R).

Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.

Prediction of Cancer Prevention: From Mammogram Screening to Identification of BRCA1/2 Mutation Carriers in Underserved Populations.

BACKGROUND: The US Preventative Service Task Force recommends that physicians perform a genetic risk assessment to identify women at risk for BRCA1/2 mutations associated with hereditary breast and ovarian cancer (HBOC) syndrome. However, outcomes data after a diagnosis of HBOC syndrome especially in diverse populations, are minimal. Here we asked if genetic screening of high-risk underserved women identified in the mammogram population reduces cancer incidence. METHODS: We evaluated 61,924 underserved women at screening mammography for family histories suggestive of HBOC syndrome over the course of 21 months. Data were collected retrospectively from patients at two safety net hospitals through chart review. A computer model was used to calculate the long-term effect of this screening on cancer incidence by assessing both the mutation detection rate and the completion of prophylactic surgeries in BRCA1/2 mutation carriers. FINDINGS: We identified 20 of the 85 (23.5%) expected BRCA1/2 mutation carriers in the underserved population. The frequencies of prophylactic mastectomies and oophorectomies in the mutation carriers were 25% and 40%, respectively. Using these data, our model predicted only an 8.8% reduction in both breast and ovarian cancer in the underserved patients. This contrasts with a 57% reduction in breast cancer and 51% reduction in ovarian cancer in an insured reference population. Our data indicate that underserved patients with HBOC syndrome are difficult to identify and when identified are limited in their ability to adhere to NCCN guidelines for cancer prevention. INTERPRETATION: Screening for women at risk for HBOC syndrome in mammogram populations will only prevent cancers if we can increase compliance with management guidelines. This study provides prototypic baseline data for step-wise analysis of the efficacy of the use of family history analysis in the mammography setting for detection and management of HBOC syndrome.

Discovery of AZD3147: a potent, selective dual inhibitor of mTORC1 and mTORC2.

High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.

Primary school teachers' attitudes about children with attention deficit/hyperactivity disorder and the role of pharmacological treatment.

BACKGROUND: Clinical experience and research suggest that teachers' attitudes about attention deficit/hyperactivity disorder (ADHD) are an important factor influencing access to specialist assessment and treatment, including medication. METHODS: We performed a thematic analysis of comments written by primary school teachers who participated in a case-vignette study investigating the ability of teachers to recognise ADHD. Teachers read one of four types of vignette describing the behaviour of a nine-year-old child who met diagnostic criteria for ADHD (either a boy or a girl with inattentive or combined subtype of ADHD). They answered questions (identical for all types of vignette) about their views regarding the problems and their management. Teachers were invited to add their own comments. RESULTS: Altogether 496 teachers from 110 schools completed the questionnaire: 250 (50%) teachers from 94 schools wrote at least one comment, adding up to 341 comments. Regarding their views on the need to refer the child to specialist services, 32 teachers made comments that reflected caution. The most frequent comments were that it was too early to say whether a referral was necessary, the problems were not severe enough or the main support would come from school. Teachers also reported a lack of knowledge about specialist services or criticised them. When asked whether medication might be beneficial for the child, 125 teachers expressed hesitant or negative views: that it was premature to express an opinion about medication or too soon to give medication to the child; that medication was not necessary or should not be used at all; or that the problems were not severe enough or were emotional in nature. Only five teachers reported having a positive experience of the effect of medication. CONCLUSION: Teachers' comments suggested a strong preference in using within-school strategies for the management of children with ADHD. Teachers were reluctant to endorse medication for DHD and expressed negative views about its use. Health services should support teachers' management of ADHD-related behaviours in school and provide information to increase teachers' ability to identify the need for a referral to specialist health services.

Protocol Evaluating the effectiveness of a school-based group programme for parents of children at risk of ADHD: the 'PArents, Teachers and CHildren WORKing Together (PATCHWORK)' cluster RCT protocol.

INTRODUCTION: Early intervention for childhood behavioural problems may help improve health and educational outcomes in affected children and reduce the likelihood of developing additional difficulties. The National Institute for Health and Clinical Excellence guidelines for attention deficit/hyperactivity disorder (ADHD), a common childhood behavioural disorder, recommend a stepped care approach for the identification and management of these problems. Parents of children with high levels of hyperactivity and inattention may benefit from intervention programmes involving behavioural management and educational approaches. Such interventions may be further enhanced by providing training and feedback to teachers about the strategies discussed with parents. In relation to children with high levels of hyperactivity, impulsiveness and inattention, we aim to test the feasibility and effectiveness of a parenting programme (with and without an accompanying teacher session) in primary schools. METHODS AND ANALYSIS: This clustered (at the level of school) randomised controlled trial (RCT) focuses on children in their first four school years (ages 4-8 years) in the East Midlands area of England. Parents will complete a screening measure, the Strengths and Difficulties Questionnaire, to identify children with high levels of hyperactivity/inattention. Three approaches to reducing hyperactivity and attention problems will be compared: a group programme for parents (parent-only intervention); group programme for parents combined with feedback to teachers (combined intervention); and waiting list control (no intervention). Differences between arms on the short version of Conners' Parent and Teacher Rating Scales Revised will be compared and also used to inform the sample size required for a future definitive cluster RCT. A preliminary cost-effectiveness analysis will also be conducted. ETHICS AND DISSEMINATION: The outcomes of this study will inform policy makers about the feasibility, acceptability and effectiveness of delivering targeted behavioural interventions within a school setting. The study has received ethical approval from the University of Nottingham Medical School Ethics Committee. TRIAL REGISTRATION: ISRCTN87634685.