Sugimoto Yasuro, Sawant Dwitiya B, Fisk Harold A, Mao Liguang, Li Chenglong, Chettiar Somsundaram, Li Pui-Kai, Darby Michael V, Brueggemeier Robert W
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Department of Molecular Genetics, College of Arts & Sciences, The Ohio State University, Columbus, OH 43210, USA.
Bioorg Med Chem. 2017 Apr 1;25(7):2156-2166. doi: 10.1016/j.bmc.2017.02.030. Epub 2017 Feb 16.
New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions. The results indicate that the lead compounds have strong anti-proliferative potential through Mps1/TTK inhibition in both basal and luminal BC cell lines, exhibiting IC values ranging from 0.05 to 1.0μM. In addition, the lead compounds 1 and 13 inhibit Mps1 kinase enzymatic activity with IC values from 0.356μM to 0.809μM, and inhibited Mps1-associated cellular functions such as centrosome duplication and the spindle checkpoint in triple negative breast cancer cells. The most promising analog, compound 13, significantly decreased tumor growth in nude mice containing Cal-51 triple negative breast cancer cell xenografts. Using drug discovery technologies, computational modeling, medicinal chemistry, cell culture and in vivo assays, novel small molecule Mps1/TTK inhibitors have been identified as potential targeted therapies for breast cancers.
人们期望针对某些亚型的乳腺癌，如三阴性乳腺癌和其他侵袭性表型，开发新的靶向治疗方法。有丝分裂检查点激酶Mps1/TTK的高表达与乳腺癌的高组织学分级相关，这表明它可能是侵袭性乳腺癌（BC）的一个新的治疗靶点。通过计算机辅助对接分析设计了靶向Mps1的新型小分子，并合成了几种候选化合物。在15种乳腺癌细胞系的抗增殖试验中对这些化合物进行了评估，并进一步检测了它们抑制多种Mps1依赖性生物学功能的能力。结果表明，先导化合物通过抑制基底型和管腔型BC细胞系中的Mps1/TTK具有很强的抗增殖潜力，IC值范围为0.05至1.0μM。此外，先导化合物1和13抑制Mps1激酶的酶活性，IC值为0.356μM至0.809μM，并抑制三阴性乳腺癌细胞中与Mps1相关的细胞功能，如中心体复制和纺锤体检查点。最有前景的类似物化合物13显著降低了含有Cal-51三阴性乳腺癌细胞异种移植物的裸鼠的肿瘤生长。通过药物发现技术、计算建模、药物化学、细胞培养和体内试验，已确定新型小分子Mps1/TTK抑制剂是乳腺癌潜在的靶向治疗药物。
