jm7b01322_si_002.pdb (363.12 kB)
Download fileDevelopment of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond
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posted 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 ShiaThe
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.
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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