Vichem Chemie Research Ltd. , Budapest 1022 , Hungary.
Institute of Physiological Chemistry , University Halle-Wittenberg , Halle (Saale) 06108 , Germany.
J Med Chem. 2018 Jul 26;61(14):6277-6292. doi: 10.1021/acs.jmedchem.8b00672. Epub 2018 Jul 9.
The overexpression of AXL kinase has been described in many types of cancer. Due to its role in proliferation, survival, migration, and resistance, AXL represents a promising target in the treatment of the disease. In this study we present a novel compound family that successfully targets the AXL kinase. Through optimization and detailed SAR studies we developed low nanomolar inhibitors, and after further biological characterization we identified a potent AXL kinase inhibitor with favorable pharmacokinetic profile. The antitumor activity was determined in xenograft models, and the lead compounds reduced the tumor size by 40% with no observed toxicity as well as lung metastasis formation by 66% when compared to vehicle control.
AXL 激酶的过表达已在许多类型的癌症中被描述。由于其在增殖、存活、迁移和耐药性方面的作用，AXL 代表了治疗该疾病的一个有前途的靶点。在这项研究中，我们提出了一个新的化合物家族，该家族成功地靶向 AXL 激酶。通过优化和详细的 SAR 研究，我们开发了低纳摩尔抑制剂，并且在进一步的生物学特性研究后，我们确定了一种具有良好药代动力学特性的有效的 AXL 激酶抑制剂。在异种移植模型中测定了抗肿瘤活性，与载体对照组相比，先导化合物使肿瘤大小缩小了 40%，并且没有观察到毒性，同时肺转移形成也减少了 66%。
