AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
J Med Chem. 2013 Mar 14;56(5):2125-38. doi: 10.1021/jm301859s. Epub 2013 Mar 1.
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.
ATR 是一个有吸引力的新型抗癌药物靶点，其抑制剂具有作为化疗或放疗增敏剂或作为特定 DNA 修复途径依赖性肿瘤的单一疗法的潜力。我们描述了一系列磺酰基吗啉嘧啶的发现和合成，这些化合物表现出强大且选择性的 ATR 抑制作用。在紧密的 SAR 空间内从高质量筛选命中进行优化，导致了化合物 6（AZ20）的产生，该化合物对从 HeLa 核提取物中免疫沉淀的 ATR 的抑制作用的 IC50 为 5 nM，并且对 HT29 结直肠腺癌肿瘤细胞中 ATR 介导的 Chk1 磷酸化的 IC50 为 50 nM。化合物 6 在体外强烈抑制 LoVo 结直肠腺癌细胞的生长，并且在中等口服剂量后在小鼠中有高的游离暴露。在耐受良好的剂量下，6 导致在裸鼠中生长的 LoVo 异种移植物的显著生长抑制。化合物 6 是一种用于体内探索 ATR 药理学的有用化合物。
