Advances in CXCR7 Modulators

Abstract

CXC chemokine receptor 7 (CXCR7) is a G-protein-coupled receptor that signals through the β-arrestin pathway. Its ligands include interferon-inducible T cell α chemoattractant (CXCL11) and stromal cell-derived factor-1 (CXCL12). It interacts with CXCR4, and the two are associated with various cancers, as well as other disease states such as coronary artery disease, stroke, inflammation and human immunodeficiency virus (HIV). Antibodies and small interfering RNA (siRNA) have shown the utility of antagonists of CXCR7 in these disease states. Although some small molecules were initially reported as antagonists due to their displayed activity, many function as agonists while still producing the desired pharmacologic effects. A potential reason for this contradiction is that effects may be due to elevated extracellular CXCL12 levels.

ACT‐1004‐1239, a first‐in‐class CXCR7 antagonist with both immunomodulatory and promyelinating effects for the treatment of inflammatory demyelinating diseases

“…Identifying CXCR7 as a potential therapeutic target in demyelinating diseases, acting both on leukocyte infiltrates and on myelin repair, has been previously reported in the literature 21,50 . However, understanding of the complex role of CXCR7 in this context has been limited by the lack of small molecule antagonists that block β‐arrestin recruitment upon CXCL11 and CXCL12 binding to CXCR7 in contrast to functional antagonists 51 . It remained unclear whether previous reported data obtained in preclinical MS models utilizing CCX771, 21,25 a small molecule CXCR7 agonist of the β‐arrestin pathway, 29 was due to its agonistic activity on CXCR7 and/or its functional antagonistic effect on CXCR7.…”

“…21,50 However, understanding of the complex role of CXCR7 in this context has been limited by the lack of small molecule antagonists that block β-arrestin recruitment upon CXCL11 and CXCL12 binding to CXCR7 in contrast to functional antagonists. 51 It remained unclear whether previous reported data obtained in preclinical MS models utilizing CCX771, 21,25 a small molecule CXCR7 agonist of the β-arrestin pathway, 29 was due to its agonistic activity on CXCR7 and/or its functional antagonistic effect on CXCR7. Indeed, previous studies reported that following the recruitment of β-arrestin, CXCR7-induced activation of downstream cell signaling pathways in different cells, including glial cells [52][53][54] which could also contribute to the efficacy observed.…”

Role of Chemokines in the Biology of Cholangiocarcinoma

“…CXCR7 expression has been observed in fetal liver cells, activated endothelial cells and various tumor cells, as well as in malignancy associated blood vessels, where CXCR7 induces cell growth, survival and increased adhesion [ 116 ].…”

“…Increased expression of CXCR7 has been observed in pancreatic, prostate, liver, ovarian, kidney, colon, breast and lung cancer [ 116 ], and in general there is a positive correlation between CXCR7 expression and tumor malignancy [ 117 ]. In addition, high expression of CXCR7 confers a high risk of developing lymph node metastasis [ 118 ].…”

Dynamical modeling predicts an inflammation-inducible CXCR7+ B cell precursor with potential implications in lymphoid blockage pathologies

“…As mentioned, CXCR7 has been extensively documented in the pathobiology of an increasing number of systemic diseases, including inflammation (rheumatoid arthritis, obesity), cancer (prostate, colon, bladder, ovarian, cervical, uterine, kidney, liver, stomach, lung, breast and hepatocelular), neurological conditions, infectious and other complex diseases, like autism and atherogenesis (reviewed in Lounsbury, 2020 ). Although for all of them destabilization of the immune system is recorded, it is uncertain whether the participation of pro-inflammatory elements is accompanied by agonist signals provided by DAMPs, PAMPs and possibly LAMPs ( Zindel & Kubes, 2020 ), and if central mechanisms are activated within the bone marrow that change the fate of developing cells or shift the identity of lymphoid niches.…”