Design, synthesis and biological evaluation of a new class of 7H-pyrrolo [2,3-d]pyrimidine derivatives as Mps1 inhibitors for the treatment of breast cancer
Design, synthesis and biological evaluation of a new class of 7H-pyrrolo [2,3-d]pyrimidine derivatives as Mps1 inhibitors for the treatment of breast cancer
复制标题
一类新型7H-吡咯并[2,3-d]嘧啶衍生物作为Mps1抑制剂治疗乳腺癌的设计、合成和生物学评价
DOI：
10.1016/j.ejmech.2022.114887
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发表时间：
2022-10-11
影响因子：
6.7
通讯作者：
Yu，Luoting
中科院分区：
文献类型：
--
作者：
Li，Xinyue;Wei，Wei;Yu，Luoting
单极纺锤体激酶1 （Monopolar spindle kinase 1, Mps1）是纺锤体组装检查点（spindle assembly checkpoint， SAC）的核心成分，在细胞从有丝分裂中期到晚期的转变中起着至关重要的作用。作为一个有吸引力的治疗靶点，抑制Mps1可诱导包括乳腺癌在内的多种肿瘤的细胞周期阻滞和细胞凋亡。然而，Mps1抑制剂的早期临床发展仍然不令人满意。在这里，我们设计并合成了一类新的具有7h -吡咯[2,3-d]嘧啶结构的Mps1抑制剂。构效关系（SAR）表明，12是一种有效的Mps1抑制剂（IC50= 29 nM），可在体外和体内抑制Mps1的磷酸化。12不仅能抑制乳腺癌细胞系的增殖，还能诱导MCF-7和4T1细胞的细胞周期阻滞和凋亡。在体内抑制肿瘤生长，无明显毒性作用。这些结果证明了Mps1抑制剂12治疗乳腺癌的潜力。
Monopolar spindle kinase 1 (Mps1), a core component of the spindle assembly checkpoint (SAC), plays a crucial role in the transition of cells from mid-to late mitosis. As an attractive therapeutic target, inhibition of Mps1 induces cell cycle arrest and apoptosis in a variety of tumors, including breast cancer. However, early clinical development of Mps1 inhibitors remains unsatisfactory. Here, we designed and synthesized a new class of Mps1 inhibitors with 7H-pyrrolo[2,3-d]pyrimidine structure using a scaffold hopping approach. Structure–activity relationship (SAR) revealed that12is a potent Mps1 inhibitor (IC50= 29 nM), which inhibited phosphorylation of Mps1in vitroandin vivo. Treatment with12not only impeded proliferation of breast cancer cell lines, but also induced cell cycle arrest and apoptosis of MCF-7 and 4T1 cells.12suppressed tumor growthin vivo, and no obvious toxicities were observed. These results demonstrated the potential of Mps1 inhibitor12for the treatment of breast cancer.