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Chemokine receptor-targeted drug discovery: progress and challenges


The chemokine receptor system is implicated in a wide range of inflammatory, autoimmune and infectious diseases (Proudfoot 2002), and in recent years attention has increasingly focused on cancer, where tumors hijack the chemokine system to provide growth and survival signals, establish and maintain an immunosuppressive tumor microenvironment, and facilitate metastatic spread (Nagarsheth, Wicha, and Zou 2017; Poeta et al. 2019).


The involvement of chemokines and their receptors in several aspects of cancer biology, represents a potential target for immunotherapy, which is reflected on the amount of ongoing clinical trials (currently 26 ongoing, completed or recruiting) (Isberg et al. 2016). Different reviews have extensively described the success and failure in drug discovery on chemokine receptors (Poeta et al. 2019). The therapeutic approaches mainly include small molecule inhibitors, as well as monoclonal antibodies and antagonist peptide analogs. There are only two drugs in the market targeting chemokine receptors: maraviroc, an allosteric and reversible inhibitor of the CCR5 used in HIV therapy; and the small molecule plerixafor, a CXCR4 antagonist used in cancer therapy (Isberg et al. 2016). The anti-CCR4 antibody mogamulizumab has also been approved in Japan and by the FDA for the treatment of mycosis fungoides or Sézary syndrome in adults which are subtypes of cutaneous T-cell lymphoma (CTCL) (Lewis and Rook 2020).


A lot of effort has been put forward to target CKRs especially in cancer, nevertheless, targeting this system is a challenging task due to its complexity and redundancy. Redundancy can be exemplified by the tumor infiltration of Treg cells which can be driven directly by different receptors (CCR4, CCR5, CCR6, CCR7, and CXCR3) and so inhibition of this process through blockade of a single receptor is hampered (O'Hayre et al. 2010). At a molecular level, different ligands bind to the same receptor and vice-versa (Marcuzzi et al. 2018). This redundancy can be seen as problematic in drug discovery as blocking a single receptor might not produce clinical efficacy. Therefore, an alternative approach is to make use of chemokine receptors redundancy and the fact that different chemokine receptors are overexpressed and promote cancer progression, and use promiscuous non-peptide antagonists able to target more than one chemokine receptor subtype, the concept of polypharmacology (Horuk 2009). On the other hand, Shall and Proudfoot excluded the idea of molecular redundancy, pointing out that, in some cases, inappropriate target selection and insufficient dosing of chemokine receptor antagonists in vivo might be the main hurdle (Schall and Proudfoot 2011). Subsequent reports characterizing small molecule agonists for CXCR3 further substantiated the notion that redundancy is not a feature of the chemokine system (Nedjai et al. 2012), but more research in different cellular contexts is needed to fully address this question.


Another important aspect in CKRs targeted drug discovery is the concept of biased agonism/antagonism, also known as functional selectivity. Drug discovery is shifting towards the development of biased ligands, which promote the engagement of the receptor with a certain effector, thus enriching a specific signaling pathway (Smith, Lefkowitz, and Rajagopal 2018). In the chemokine-receptor system, different chemokines are able to activate different pathways, which can also vary depending on the cell and tissue context. Signaling bias can be seen as complex as advantageous since selectively inhibiting certain signaling pathways while sparing others, can prevent some of the negative off-target effects. An example is CCL5 which binds to CCR1, CCR3 and CCR5, and induces different patterns of receptor recycling where CCR5 recycles back to the cell surface (Mack et al. 1998), CCR3 is partially restored to the cell surface and partially targeted to lysosomes (Zimmermann, Conkright, and Rothenberg 1999) and CCR1 does not recycle (Elsner et al. 2001).


Furthermore, both chemokines and receptors can homo- and hetero-oligomerize, impacting receptor/ligand-binding and signaling patterns, by modulating ligand binding, as well as G-protein coupling or interaction with other signaling molecules (Sohy et al. 2009; Wang and Norcross 2008). Therefore, the in vivo state of the receptor and its existence as homo and herero-oligomeres at the cell surface should be considered when assessing the pharmacological profile of new compounds.


Moreover, it is difficult to demonstrate clinical efficacy with a specific antagonist to a single receptor as patients cannot be stratified into CKRs specific subpopulations for a specific disease (Horuk 2009). Further difficulties arise from the existence of cross-reactivity with other GPCRs and differences in the chemokine systems between species which, in some cases, hampers the pre-clinical development (Marcuzzi et al. 2018). In fact, the requirements in terms of safety margin, oral bioavailability, and frequency of administration are particularly rigorous for this class, as the majority of potential therapeutic applications are situated in the area of chronic inflammatory disease (Proudfoot, Power, and Schwarz 2010).


An additional milestone is represented by the large binding pocket of chemokine receptors which are regulated by globular protein ligands, unlike most of the class A GPCRs ligands that are small molecules or short peptides. These larger interfaces represent the typical protein-protein interactions which are difficult to modulate using small molecules (Sohy et al. 2009; Wang and Norcross 2008); and are also too small to be engaged by antibodies, which can only interact with the extracellular domain of the receptor ((Zimmermann, Conkright, and Rothenberg 1999). A promising strategy corresponds to the use of engineered chemokine analogs which are analogs of the natural ligands, allowing a better molecular fit with the binding pocket (Paolini-Bertrand et al. 2018).


Overall, the future potential lies in using different therapeutic modalities to modulate the stromal component, overcome chemotherapy resistance, and optimize immune responses and a comprehensive understanding of the role of the chemokine receptor system in different malignancies is crucial to avoid potential side effects and enhance the efficacy of immunotherapeutic strategies.

 


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