jm7b01322_si_002.pdb (363.12 kB)
Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond
datasetposted on 2018-01-09, 00:00 authored by Chien-Huang Wu, Jen-Shin Song, Hsuan-Hao Kuan, Szu-Huei Wu, Ming-Chen Chou, Jiing-Jyh Jan, Lun K. Tsou, Yi-Yu Ke, Chiung-Tong Chen, Kai-Chia Yeh, Sing-Yi Wang, Teng-Kuang Yeh, Chen-Tso Tseng, Chen-Lung Huang, Mine-Hsine Wu, Po-Chu Kuo, Chia-Jui Lee, Kak-Shan Shia
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 16 into 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.
cancer metastasisCXCR 4bone marrowdrug candidatePeripheral Blood Stem Cell Transplantationresponse doseAMDHSC-mobilizing abilitybinding modedisease indicationspyrimidine-based CXCR 4 antagonistsPBSCT indicationdrug 1spider-like conformationnovel seriesDocking compound 16Blocking CXCR 4X-ray crystal structureStem-Cell-Mobilizing Agents Targeting CXCR 4 Receptorcell typesCXCR 4 receptor