Targeting chemokine receptors in disease--a case study of CCR4

Abstract

Since their early 1990s, the chemokine receptor family of G protein-coupled receptors (GPCRs) has been the source of much pharmacological endeavour. Best known for their key roles in recruiting leukocytes to sites of infection and inflammation, the receptors present themselves as plausible drug targets for therapeutic intervention. In this article, we will focus our attention upon CC Chemokine Receptor Four (CCR4) which has been implicated in diseases as diverse as allergic asthma and lymphoma. We will review the discovery of the receptors and their ligands, their perceived roles in disease and the successful targeting of CCR4 by both small molecule antagonists and monoclonal antibodies. We will also discuss future directions and strategies for drug discovery in this field.

Keywords: Antagonist; Asthma leukaemia; Chemokine; Inflammation; Receptor; Signaling.

Fig. 1

Cartoon showing a leukocyte migrating along a gradient of chemokine (gray) in the direction of the arrow. Activation of the 7TMRs at the leading edge of the cell activated PI3K to PIP₃. The location of the phosphatase PTEN at the rear of the cell results in an internal gradient of PIP₃ , which is concentrated in the vicinity of the receptor. This facilitates localized binding of Rho GTPases such as Cdc42 and Rac (blue, green pink ovals) which modulate the actin cytoskeleton and contribute to membrane protrusion in the direction of the chemokine source.

Fig. 2

The chemical structures of a handful of small molecule CCR4 antagonists described in the main text.

Fig. 3

A diagram representing various modes of allosteric modulation at CCR4. The left panels shows transmembrane helices II and III of CCR4 being activated by chemokine (space filled model). The centre panel shows a "Site 1" antagonist (yellow) bound to an intrahelical binding site. The right panel shows a lipophillic "Site 2" antagonist (cyan) interacting with C-terminal helix VIII of CCR4.