Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; School of Life Science and Technology, Shanghai Tech University, 393 Middle Huaxia Road, Pudong New District, Shanghai, 201210, China.
Eur J Med Chem. 2021 Aug 5;220:113497. doi: 10.1016/j.ejmech.2021.113497. Epub 2021 Apr 25.
Axl has emerged as an attractive target for cancer therapy due to its strong correlation with tumor growth, metastasis, poor survival, and drug resistance. Herein, we report the design, synthesis and structure-activity relationship (SAR) investigation of a series of pyrrolo[2,3-d]pyrimidine derivatives as new Axl inhibitors. Among them, the most promising compound 13b showed high enzymatic and cellular Axl potencies. Furthermore, 13b possessed preferable pharmacokinetic properties and displayed promising therapeutic effect in BaF3/TEL-Axl xenograft tumor model. Compound 13b may serve as a lead compound for new antitumor drug discovery.
Axl 由于与肿瘤生长、转移、不良生存和耐药性密切相关，已成为癌症治疗的一个有吸引力的靶点。在此，我们报告了一系列吡咯并[2,3-d]嘧啶衍生物作为新型 Axl 抑制剂的设计、合成和构效关系（SAR）研究。其中，最有前途的化合物 13b 表现出高的酶和细胞 Axl 活性。此外，13b 具有较好的药代动力学特性，并在 BaF3/TEL-Axl 异种移植肿瘤模型中显示出有希望的治疗效果。化合物 13b 可能成为新型抗肿瘤药物发现的先导化合物。
