Targeting CC chemokine receptor 2:
From insurmountable antagonists to affinity-based probes
In early drug discovery pharmaceutical companies optimize the properties of drug candidates for a given therapeutic target, focusing on standard pharmacological parameters of affinity, potency and intrinsic activity. Despite these intensive efforts, the success rate of a candidate drug moving to the pre-clinical development phase is disappointingly low.
We have recently focused on the chemokine receptor CCR2, which is a G protein-coupled receptor – an important family of drug targets. This receptor is primarily activated by the endogenous chemokine CCL2. Several small molecule antagonists have been developed to inhibit this receptor, as it is involved in many diseases characterized by chronic inflammation. Unfortunately, all these antagonists lack clinical efficacy warranting a better understanding of their mechanism of action.
During this talk, I will show how our work on novel drug discovery concepts (e.g. target binding kinetics and allosteric modulation) and novel tools, such as an AfBP, contributes to this understanding, and how they open new avenues for CCR2, and GPCR small molecule drug discovery.
 Ortiz Zacarías NV et al. Design and Characterization of an Intracellular Covalent Ligand for CC Chemokine Receptor 2. J Med Chem. 2021, 64, 2608
 Zheng Y et al. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature. 2016, 540, 458
 Yang X et al. An Affinity-Based Probe for the Human Adenosine A2A Receptor. J Med Chem. 2018, 61, 7892