Dimitrov Teodor, Anli Cetin, Moschopoulou Athina Anastasia, Kronenberger Thales, Kudolo Mark, Geibel Christian, Schwalm Martin Peter, Knapp Stefan, Zender Lars, Forster Michael, Laufer Stefan
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076, Tübingen, Germany.
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany.
Eur J Med Chem. 2022 May 5;235:114234. doi: 10.1016/j.ejmech.2022.114234. Epub 2022 Mar 8.
The ATM kinase is a key molecule regulating DNA damage response and can be targeted resulting in efficient radio- or chemosensitization. Due to the enormous size of this protein and the associated difficulties in obtaining high-quality crystal structures, we sought to develop an accurate in silico model to identify new targeting possibilities. We identified a urea group as the most beneficial chemical anchor point, which could undergo multiple interactions in the aspartate-rich hydrophobic region I of the atypical ATM kinase domain. Based on in silico data, we designed and synthesized a comprehensive set of novel urea-based inhibitors and characterized them in diverse biochemical assays. Using this strategy, we identified inhibitors with subnanomolar potency, which were further evaluated in cellular models, selectivity and early DMPK properties. Finally, the two lead compounds 34 and 39 exhibited subnanomolar cellular activity along with an excellent selectivity profile and favorable metabolic stability.
ATM激酶是调节DNA损伤反应的关键分子，可作为靶点实现有效的放射或化学增敏作用。由于该蛋白质体积巨大，且难以获得高质量的晶体结构，我们试图开发一种精确的计算机模拟模型，以确定新的靶向可能性。我们确定脲基是最有利的化学锚点，它可在非典型ATM激酶结构域富含天冬氨酸的疏水区域I中发生多种相互作用。基于计算机模拟数据，我们设计并合成了一系列新型脲基抑制剂，并在多种生化分析中对其进行了表征。采用该策略，我们鉴定出了具有亚纳摩尔效力的抑制剂，并在细胞模型、选择性和早期药物代谢动力学性质方面对其进行了进一步评估。最后，两种先导化合物34和39表现出亚纳摩尔的细胞活性，以及优异的选择性和良好的代谢稳定性。
