Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent.

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.

Benefits of mTOR kinase targeting in oncology: pre-clinical evidence with AZD8055.

AZD8055 is a small-molecule inhibitor of mTOR (mammalian target of rapamycin) kinase activity. The present review highlights molecular and phenotypic differences between AZD8055 and allosteric inhibitors of mTOR such as rapamycin. Biomarkers, some of which are applicable to clinical studies, as well as biological effects such as autophagy, growth inhibition and cell death are compared between AZD8055 and rapamycin. Potential ways to develop rational combinations with mTOR kinase inhibitors are also discussed. Overall, AZD8055 may provide a better therapeutic strategy than rapamycin and analogues.

Evaluation of a convenient method of assessing rodent visual function in safety pharmacology studies: effects of sodium iodate on visual acuity and retinal morphology in albino and pigmented rats and mice.

INTRODUCTION: We have evaluated the ability of a semi-automated, optomotor reflex method to assess drug-induced visual dysfunction, in albino and pigmented rats and mice. METHODS: Male Han Wistar (HW) and Long Evans (LE) rats and mice (CD-1 and C57BL/6) were tested in a chamber formed by 4 computer monitors displaying a rotating vertical grating, to elicit head-tracking movements. The highest visible grating frequency was taken as the threshold of visual acuity, in cycles per degree (c/d). Animals received an intravenous infusion of either sodium iodate (50mg/kg) or 0.9% w/v NaCl (aq). They were tested 2h later, then re-tested daily for a further 3 days. The time course of the effect was assessed in HW rats over a 6-week period, including electron microscopy, and immunohistochemical analysis of markers of injury and repair in the retina. RESULTS: Baseline visual acuities for HW and LE rats were 0.355 ± 0.007 and 0.530 ± 0.004 c/d, respectively, and 0.296 ± 0.003 c/d and 0.370 ± 0.001 c/d for CD-1 and C57BL/6 mice, respectively (n=10 for each). In HW rats there was a dramatic loss of visual acuity 2h after administration of sodium iodate (0.021 ± 0.021 c/d; P<0.001). Less dramatic decreases in visual acuity were seen in LE rats and in the two mouse strains. In HW rats, visual acuity was restored after 4 weeks. This paralleled the histopathological recovery of the peripheral retina, whereas the central retina did not recover. DISCUSSION: The method proved to be very convenient, and the stability of visual acuity in vehicle control rats over a 6-week period also demonstrated its suitability for inclusion in long-term toxicity studies. Both albino and pigmented mice and rats are suitable for assessment of retinotoxicity using this method, but albino rats are the most sensitive to sodium iodate.