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

Eur J Med Chem. 2023 Jan 5;245(Pt 1):114887. doi: 10.1016/j.ejmech.2022.114887.

Xinyue Li ¹, Wei Wei ¹, Longyue Tao ¹, Jun Zeng ¹, Yongxia Zhu ², Tianqiong Yang ¹, Qiwei Wang ¹, Minhai Tang ¹, Zhihao Liu ³, Luoting Yu ⁴

Affiliations

1 Laboratory of Emergency Medicine, Department of Emergency Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
2 Department of Clinical Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.
3 Laboratory of Emergency Medicine, Department of Emergency Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
4 Laboratory of Emergency Medicine, Department of Emergency Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].

PMID: 36370549 DOI: 10.1016/j.ejmech.2022.114887

Abstract

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 that 12 is a potent Mps1 Inhibitor (IC₅₀ = 29 nM), which inhibited phosphorylation of Mps1 in vitro and in vivo. Treatment with 12 not only impeded proliferation of breast Cancer cell lines, but also induced cell cycle arrest and Apoptosis of MCF-7 and 4T1 cells. 12 suppressed tumor growth in vivo, and no obvious toxicities were observed. These results demonstrated the potential of Mps1 Inhibitor 12 for the treatment of breast Cancer.

Keywords

Anti-Tumor; Breast cancer; Kinase inhibitor; Mps1; Structure-activity relationship.

Name
Email *

	Sorry, but the email address you supplied was invalid.