The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress.Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.

ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.

Obesity and eating disorders (EDs) are both prevalent in adolescents. There are concerns that obesity prevention efforts may lead to the development of an ED. Most adolescents who develop an ED did not have obesity previously, but some teenagers, in an attempt to lose weight, may develop an ED. This clinical report addresses the interaction between obesity prevention and EDs in teenagers, provides the pediatrician with evidence-informed tools to identify behaviors that predispose to both obesity and EDs, and provides guidance about obesity and ED prevention messages. The focus should be on a healthy lifestyle rather than on weight. Evidence suggests that obesity prevention and treatment, if conducted correctly, do not predispose to EDs.

Consumption of sugary beverages has been identified as a contributor to childhood obesity. Studies have established the importance of specific parenting practices to children's beverage consumption; however, no study has examined multiple operationalizations of parenting to better understand where to focus future interventions. The present study examined the relationship between children's sugary beverage consumption and a parenting model that included household food rules, parent modeling of food rules, parent-mediated behaviors, and parent support. Baseline data from Project MOVE/me Muevo were used. Participants included 541 children, aged 5 to 8 years old, and their parents. Parents completed a 45-minute self-administered survey in Spanish or English, providing information about their child's dietary intake, as well as their parenting practices. Children's sugary beverage consumption included nondiet soda, noncarbonated sugary drinks, and sport drinks. Household food rules and parent modeling of food rules were assessed with seven items each. Parent-mediated behaviors consisted of four behaviors. Parent support was assessed with five items. Parent support and parent-mediated behaviors, including total screen time and eating at fast-food restaurants at least weekly, were associated with greater consumption of sugary beverages in children. No other parenting variables were significant. Encouraging caregivers to promote healthy dietary behaviors and provide healthy choices, limiting children's television and computer use, and reducing fast-food consumption can contribute to reductions in sugary beverage consumption among children.

AZD6738 is a potent and selective inhibitor of ataxia telangiectasia and rad3 related (ATR) kinase with the potential to be used in the clinic. We report the discovery of a morpholino-pyrimidine series and its subsequent optimisation to the pre-clinical candidate AZD6738 which has a good overall balance of potency, selectivity, pharmacokinetic and biopharmaceutical properties suitable for oral dosing. ATR is a serine/threonine protein kinase involved in DNA damage response signalling caused by DNA replication associated stress. Activation of ATR at stalled replication forks leads to suppression of replication fork origin firing, promotes repair and S/G2-cell cycle checkpoints to prevent premature mitosis and maintain genomic integrity. Failure to resolve damage leads to genomic instability and if sufficiently high, cell death. Stalled replication forks may collapse leading to formation of DNA double stranded breaks and activation of the ataxia telangiectasia mutated (ATM) kinase. ATM works in conjunction with ATR to efficiently resolve replication associated DNA damage creating a co-dependency with loss of one leading to a greater reliance on the other to maintain genomic stability. ATM is frequently inactivated across B-cell malignancies, head and neck, breast and lung cancers through chromosomal deletion, promoter hypermethylation or mutation. ATM-deficient tumours are hypothesised to be more reliant on ATR for survival and specific inhibition of ATR may lead enhanced anti-tumour activity while minimizing normal tissue toxicity. AZD6378 has the potential to test the clinical efficacy of ATR inhibition in cancer patients as monotherapy against ATM-deficient tumours or in combination with chemo or radiotherapy. Citation Format: Clifford D. Jones, Kevin Blades, Kevin M. Foote, Sylvie M. Guichard, Philip J. Jewsbury, Thomas McGuire, Johannes W. Nissink, Rajesh Odedra, Kin Tam, Pia Thommes, Paul Turner, Gary Wilkinson, Christine Wood, James W. Yates. Discovery of AZD6738, a potent and selective inhibitor with the potential to test the clinical efficacy of ATR kinase inhibition in cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2348. doi:10.1158/1538-7445.AM2013-2348