Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond

J Med Chem. 2018 Feb 8;61(3):818-833. doi: 10.1021/acs.jmedchem.7b01322.

Chien-Huang Wu ¹, Jen-Shin Song ¹, Hsuan-Hao Kuan ¹, Szu-Huei Wu ¹, Ming-Chen Chou ¹, Jiing-Jyh Jan ¹, Lun K Tsou ¹, Yi-Yu Ke ¹, Chiung-Tong Chen ¹, Kai-Chia Yeh ¹, Sing-Yi Wang ¹, Teng-Kuang Yeh ¹, Chen-Tso Tseng ¹, Chen-Lung Huang ¹, Mine-Hsine Wu ¹, Po-Chu Kuo ¹, Chia-Jui Lee ¹, Kak-Shan Shia ¹

Affiliations

Affiliation

1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Miaoli County 35053, Taiwan, R.O.C.

PMID: 29314840 DOI: 10.1021/acs.jmedchem.7b01322

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.

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