Cancer Research UK Centre for Cancer Therapeutics , The Institute of Cancer Research , 15 Cotswold Road , London SM2 5NG , United Kingdom.
J Med Chem. 2019 Jun 27;62(12):5863-5884. doi: 10.1021/acs.jmedchem.9b00335. Epub 2019 May 23.
Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that cross-links collagens and elastin in the extracellular matrix and is a critical mediator of tumor growth and metastatic spread. LOX is a target for cancer therapy, and thus the search for therapeutic agents against LOX has been widely sought. We report herein the medicinal chemistry discovery of a series of LOX inhibitors bearing an aminomethylenethiophene (AMT) scaffold. High-throughput screening provided the initial hits. Structure-activity relationship (SAR) studies led to the discovery of AMT inhibitors with sub-micromolar half-maximal inhibitory concentrations (IC) in a LOX enzyme activity assay. Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy.
赖氨酰氧化酶（LOX）是一种分泌型铜依赖性胺氧化酶，可在细胞外基质中交联胶原蛋白和弹性蛋白，是肿瘤生长和转移扩散的关键介质。LOX 是癌症治疗的靶点，因此，人们广泛寻求针对 LOX 的治疗剂。我们在此报告了一系列含有氨甲基噻吩（AMT）支架的 LOX 抑制剂的药物化学发现。高通量筛选提供了最初的命中结果。结构-活性关系（SAR）研究导致发现了在 LOX 酶活性测定中具有亚微摩尔半数最大抑制浓度（IC）的 AMT 抑制剂。进一步的 SAR 优化得到了口服生物利用度的 LOX 抑制剂 CCT365623，具有良好的抗 LOX 效力、选择性、药代动力学特性以及抗转移功效。
