Drug discovery research targeting the CXC chemokine receptor 4 (CXCR4).

Chemokines are small 70 amino acid long soluble proteins that chemoattract a variety of mononuclear cell types to sites of inflammation or secondary lymphoid organs by interacting with chemokine receptors. 1 They are divided into four subfamilies of CC, CXC, CX3C, and C chemokines based on the positions of two conserved cysteine residues in their amino (N)-termini. 2,3 The CXC chemokine receptor 4 (CXCR4) is an attractive target for therapeutic intervention because of its involvement in the pathogeneses of a wide range of infectious, inflammatory, and other diseases. CXCR4 is a transmembrane (TM) protein that belongs to the superfamily of G-protein-coupled receptors (GPCRs). 2,4,5 It possesses seven TM helices and transmits signals from its natural chemokine ligand, stromal cell-derived factor (SDF)-1α/CXCL12, to intracellular biological pathways via heterotrimeric G-proteins. The activation of CXCR4 by SDF-1α can trigger different downstream signaling pathways that result in a variety of physiological responses, such as chemotaxis, cell survival and proliferation, intracellular calcium flux, and gene transcription (Fig. 1). 6-15 These normal physiological responses also share several downstream effectors with multiple pathological processes, including tumor cell metastasis, and autoimmune and inflammatory diseases. For instance, CXCR-mediated chemotaxis and cell survival involves PI3 kinase (PI3K) which also plays a major role in cancer cell survival, proliferation, and metastasis. 10 Whereas cancer cell proliferation requires the activation of Akt (serine/threonine protein kinase) via the PI3K pathway, physiologically occurring cell survival can activate Bcl-2-associated death promoter (BAD) via both MEK (MAP kinase kinase) and PI3K pathways, which leads to the inhibition of the proapoptotic protein Bcl-2. 6 Similarly, although Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway allows a G-protein independent signaling pathway via CXCR4, the receptor phosphorylation by JAK2 and JAK3 leads to the activation and nuclear translocation of a variety of STAT proteins, which leads to cancer cell survival and proliferation.16 Figure 1 CXCR4 intracellular signaling pathways. CXCR4 activation by SDF-1α can trigger a variety of physiological responses, such as chemotaxis, cell survival and proliferation, intracellular calcium flux, and gene transcription, whereas CXCR4 antagonists ... The structures of multiple chemokines have been determined by NMR or X-ray crystallography, including those of SDF-1α, 17,18 viral macrophage inflammatory protein (vMIP)-II, 19,20 macrophage inflammatory protein (MIP)-1β, 21 and ‘regulated on activation, normal T-cell expressed and secreted’ (RANTES). 22 These structures demonstrate the highly conserved three-dimensional structures of all chemokines, including a flexible N-terminus, a three-stranded anti-parallel β-sheet, and a C-terminal α-helix. 23 In the typical structure, the first two cysteine residues are situated close together near the amino (N)-terminus, with the third cysteine residue residing in the center of the molecule, and the fourth cysteine residue located close to the carboxyl (C)-terminal end. 24 An “N-loop” of approximately ten amino acids follows the first two cysteine residues. Following the N-loop, there is a single-turn “310-helix,” a β-sheet with three β-strands, and a C-terminal α-helix, connected by turns called “30s,” “40s,” and “50s” loops. The third and fourth cysteine residues are located in the 30s and 50s loops, respectively. Due to its involvement in a wide range of physiological and pathologic processes, there has been intensive biological, chemical, and pharmaceutical research to understand the molecular mechanisms of chemokine–receptor interactions and the modulation of chemokine–receptor functions. The ultimate goal is to translate these discoveries into novel treatment strategies for clinical applications. This review describes and discusses some of the recent advances in medicinal chemistry and drug discovery that involve CXCR4, which is implicated in human immunodeficiency virus (HIV)-1 infection, normal hematopoietic and neural stem cell migration, cancer–stromal cell interaction, solid tumors, and inflammation and autoimmune diseases such as rheumatoid arthritis and allergic asthma.