Discovery of small molecule CXCR4 antagonists.

Journal of medicinal chemistry (2007-10-26)
Weiqiang Zhan, Zhongxing Liang, Aizhi Zhu, Serdar Kurtkaya, Hyunsuk Shim, James P Snyder, Dennis C Liotta
ABSTRACT

In light of a proposed molecular mechanism for the C-X-C chemokine receptor type 4 (CXCR4) antagonist 1 (AMD3100), a template with the general structure 2 was designed, and 15 was identified as a lead by means of an affinity binding assay against the ligand-mimicking CXCR4 antagonist 3 (TN14003). Following a structure-activity profile around 15, the design and synthesis of a series of novel small molecular CXCR4 antagonists led to the discovery of 32 (WZ811). The compound shows subnanomolar potency (EC50 = 0.3 nM) in an affinity binding assay. In addition, when subjected to in vitro functional evaluation, 32 efficiently inhibits CXCR4/stromal cell-derived factor-1 (SDF-1)-mediated modulation of cyclic adenosine monophophate (cAMP) levels (EC50 = 1.2 nM) and SDF-1 induced Matrigel invasion (EC50 = 5.2 nM). Molecular field topology analysis (MFTA), a 2D quantitative structure-activity relationship (QSAR) approach based on local molecular properties (Van der Waals radii (VdW), atomic charges, and local lipophilicity), applied to the 32 series suggests structural modifications to improve potency.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
p-Xylylenediamine, 99%
Sigma-Aldrich
2-Methylthio-2-imidazoline hydriodide, 99%
Sigma-Aldrich
Stromal Cell-Derived Factor 1α/pre-B Cell Growth Stimulating Factor human, recombinant, expressed in E. coli, lyophilized powder, ≥97% (SDS-PAGE), suitable for cell culture
Sigma-Aldrich
WZ811, ≥98% (HPLC)

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