Liu Yang, Peng Xia, Guan Xiaocong, Lu Dong, Xi Yong, Jin Shiyu, Chen Hui, Zeng Limin, Ai Jing, Geng Meiyu, Hu Youhong
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
Eur J Med Chem. 2017 Jan 27;126:122-132. doi: 10.1016/j.ejmech.2016.10.003. Epub 2016 Oct 4.
FGF receptors (FGFRs) are tyrosine kinases that are overexpressed in diverse tumors by genetic alterations such as gene amplifications, somatic mutations and translocations. Owing to this characteristic, FGFRs are attractive targets for cancer treatment. It has been demonstrated that most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The design of new and more selective inhibitors of FGFRs, which might be reduced off-target and side effects, is a difficult yet significant challenge. The results of the current investigation, show that novel Ponatinib analogues are highly active as FGFR inhibitors and that they possess reduced kinase insert domain receptor (KDR) activities. Observations made in a structure and activity relationship (SAR) investigation led to the development of a promising, orally available lead compound 4, which displays a 50-100 fold in vitro selectivity for inhibition of FGFR1-3 over KDR. In addition, biological evaluation of compound 4 showed that it displays significant antitumor activities in FGFR1-amplificated H1581 and FGFR2-amplificated SNU-16 xenograft models.
成纤维细胞生长因子受体（FGFRs）是酪氨酸激酶，在多种肿瘤中因基因扩增、体细胞突变和易位等基因改变而过度表达。由于这一特性，FGFRs成为癌症治疗的有吸引力的靶点。已证明，大多数多靶点、ATP竞争性酪氨酸激酶抑制剂对FGFRs以及其他激酶均有活性。设计新型且更具选择性的FGFRs抑制剂，以减少脱靶效应和副作用，是一项艰巨但意义重大的挑战。当前研究结果表明，新型波纳替尼类似物作为FGFR抑制剂具有高活性，且其激酶插入结构域受体（KDR）活性降低。在结构与活性关系（SAR）研究中的观察结果导致开发出一种有前景的口服活性先导化合物4，其对FGFR1 - 3的体外抑制选择性比对KDR高50 - 100倍。此外，化合物4的生物学评估表明，它在FGFR1扩增的H1581和FGFR2扩增的SNU - 16异种移植模型中显示出显著的抗肿瘤活性。
