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Review
. 2024 Jul 12:15:1410104.
doi: 10.3389/fphar.2024.1410104. eCollection 2024.

The story of clobenpropit and CXCR4: can be an effective drug in cancer and autoimmune diseases?

Mitra Abbasifard  1 , Kowsar Bagherzadeh  2 , Hossein Khorramdelazad  3
Affiliations
Review

The story of clobenpropit and CXCR4: can be an effective drug in cancer and autoimmune diseases?

Mitra Abbasifard et al. Front Pharmacol. .

Abstract

Clobenpropit is a histamine H3 receptor antagonist and has developed as a potential therapeutic drug due to its ability to inhibit CXCR4, a chemokine receptor involved in autoimmune diseases and cancer pathogenesis. The CXCL12/CXCR4 axis involves several biological phenomena, including cell proliferation, migration, angiogenesis, inflammation, and metastasis. Accordingly, inhibiting CXCR4 can have promising clinical outcomes in patients with malignancy or autoimmune disorders. Based on available knowledge, Clobenpropit can effectively regulate the release of monocyte-derived inflammatory cytokine in autoimmune diseases such as juvenile idiopathic arthritis (JIA), presenting a potential targeted target with possible advantages over current therapeutic approaches. This review summarizes the intricate interplay between Clobenpropit and CXCR4 and the molecular mechanisms underlying their interactions, comprehensively analyzing their impact on immune regulation. Furthermore, we discuss preclinical and clinical investigations highlighting the probable efficacy of Clobenpropit for managing autoimmune diseases and cancer. Through this study, we aim to clarify the immunomodulatory role of Clobenpropit and its advantages and disadvantages as a novel therapeutic opportunity.

Keywords: CXCL12 (SDF-1α); CXCR4; autoimmune disease; cancer; clobenpropit.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The CXCL12/CXCR4 signaling pathway. The downstream pathways are shown with violet lines (source: KEGG, https://www.kegg.jp/pathway/hsa04062+N01765).
FIGURE 2
FIGURE 2
CXCR4 protein interactions (source: STRING, https://stringdb.org/cgi/network?taskId=bT78SZ6aKg1s&sessionId=b9z8Gu1eenbw&allnodes=1).
FIGURE 3
FIGURE 3
The role of/CXCL12CXCR4 axis in the TME. The critical features of the TME influence cancer progression. The TME is characterized by hypoxia, high acidity, and expression of inhibitory immune checkpoints such as PD-1/PD-L1, CTLA-4, LAG-3, TIM-3, TIGIT, and VISTA. Additionally, immunosuppressive cells like Tregs, TAMs, CAFs, and MDSCs are recruited, suppressing anti-tumor immune responses via secreting immunosuppressive cytokines, such as IL-10, IL-35, and TGF-β. Chemokines, particularly the dysregulated CXCL12/CXCR4 axis, play a role in recruiting regulatory and cancer-associated cells to the TME. The CXCR4 receptor, upregulated in hypoxic conditions, induces angiogenesis through the PI3K/AKT pathway, contributing to tumor progression by promoting VEGF expression. This axis is implicated in both tumor angiogenesis and metastasis to distant organs.
FIGURE 4
FIGURE 4
Dysregulation of the CXCL12/CXCR4 axis in ADs.
FIGURE 5
FIGURE 5
Histamine/histamine receptors and the CXCL12/CXCR4 axis. Clobenpropit binds to H3/H4 and CXCR4 receptors and can inhibit the downstream pathways. Inhibition of these receptors can lead to a decrease in cell proliferation, migration, and production of cytokines, which are used in the treatment of cancer and ADs.
FIGURE 6
FIGURE 6
The overall structure of CXCR4 (monomer) and the CXCR4 binding site (groove) for CXCL12 along with a close view of Clobenpropit interactions with CXCR4. Green dashes represent salt bridges and velvet dashes represent π- π stacked and π- π T-shaped electrostatic interactions.
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