Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Miaoli County 35053, Taiwan, R.O.C.
J Med Chem. 2018 Feb 8;61(3):818-833. doi: 10.1021/acs.jmedchem.7b01322. Epub 2018 Jan 27.
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.
CXCR4/CXCL12 轴的功能涉及许多疾病适应症，包括组织/神经再生、癌症转移和炎症。用其拮抗剂阻断 CXCR4 信号可能导致 CXCR4 细胞类型从骨髓转移到外周循环。我们发现了一系列新型嘧啶基 CXCR4 拮抗剂，其中一个代表性化合物（即 16）在较高剂量下具有更好的耐受性，并且在最大反应剂量下显示出比已批准药物 1（AMD3100）更好的造血干细胞动员能力，因此被认为是用于 PBSCT 适应症的潜在药物候选物。将化合物 16 对接入 CXCR4 受体的 X 射线晶体结构中表明，它采用了一种蜘蛛样构象，跨越主要和次要亚口袋。这种假定的结合模式为进一步的结构修饰提供了对 CXCR4 受体-配体相互作用的新见解。
