1. Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond
- Author
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Wu, Chien-Huang, Song, Jen-Shin, Kuan, Hsuan-Hao, Wu, Szu-Huei, Chou, Ming-Chen, Jan, Jiing-Jyh, Tsou, Lun K., Ke, Yi-Yu, Chen, Chiung-Tong, Yeh, Kai-Chia, Wang, Sing-Yi, Yeh, Teng-Kuang, Tseng, Chen-Tso, Huang, Chen-Lung, Wu, Mine-Hsine, Kuo, Po-Chu, Lee, Chia-Jui, and Shia, Kak-Shan
- Abstract
The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4+cell types from bone marrow to peripheral circulation. We have discovered a novel series of pyrimidine-based CXCR4 antagonists, a representative (i.e., 16) of which was tolerated at a higher dose and showed better HSC-mobilizing ability at the maximal response dose relative to the approved drug 1(AMD3100), and thus considered a potential drug candidate for PBSCT indication. Docking compound 16into the X-ray crystal structure of CXCR4 receptor revealed that it adopted a spider-like conformation striding over both major and minor subpockets. This putative binding mode provides a new insight into CXCR4 receptor–ligand interactions for further structural modifications.
- Published
- 2024
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