Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors,Journal of Medicinal Chemistry

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Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-06-21 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00672
István Szabadkai ₁ , Robert Torka ₂ , Rita Garamvölgyi _{1,

3} , Ferenc Baska ₁ , Pál Gyulavári ₄ , Sándor Boros ₁ , Eszter Illyés ₁ , Axel Choidas ₅ , Axel Ullrich ₆ , László Őrfi _{1,

3}

Affiliation

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.

中文翻译：

发现 N-[4-(喹啉-4-基氧基)苯基]苯磺酰胺作为新型 AXL 激酶抑制剂

AXL 激酶的过度表达已在多种类型的癌症中得到描述。由于其在增殖、存活、迁移和耐药性中的作用，AXL 代表了该疾病治疗的一个有前途的靶点。在这项研究中，我们提出了一个成功靶向 AXL 激酶的新型化合物家族。通过优化和详细的 SAR 研究，我们开发了低纳摩尔抑制剂，经过进一步的生物学表征，我们确定了一种具有良好药代动力学特征的有效 AXL 激酶抑制剂。在异种移植模型中测定了抗肿瘤活性，与载体对照相比，先导化合物使肿瘤大小减少了 40%，且未观察到毒性，并且肺转移形成减少了 66%。

更新日期：2018-06-21

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