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ID: ALA4024793
Journal: J Med Chem
Title: Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond.
Authors: Wu CH, Song JS, Kuan HH, Wu SH, Chou MC, Jan JJ, Tsou LK, Ke YY, Chen CT, Yeh KC, Wang SY, Yeh TK, Tseng CT, Huang CL, Wu MH, Kuo PC, Lee CJ, Shia KS.
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 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.
CiteXplore: 29314840