Keung Walter, Boloor Amogh, Brown Jason, Kiryanov Andre, Gangloff Anthony, Lawson J David, Skene Robert, Hoffman Isaac, Atienza Josephine, Kahana Jason, De Jong Ron, Farrell Pamela, Balakrishna Deepika, Halkowycz Petro
Medicinal Chemistry, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
Medicinal Chemistry, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
Bioorg Med Chem Lett. 2017 Feb 15;27(4):1099-1104. doi: 10.1016/j.bmcl.2016.12.024. Epub 2016 Dec 20.
Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies.
基于Axl在各种致癌过程中的作用，多年来它一直是肿瘤学领域的关注靶点。迄今为止，尚未有野生型Axl晶体结构的报道。在此，我们描述了一种新型Axl抑制剂化学类型1H-咪唑-2-甲酰胺基于结构的优化，使用突变的激酶同源物Mer(I650M)作为晶体学替代物。对初始先导化合物(1)进行迭代优化得到化合物(21)，它是野生型Axl的一种选择性强效抑制剂。化合物(21)将作为进一步体内研究的有用化合物。
