Targeting chemokine receptors from the inside-out: discovery and development of small-molecule intracellular antagonists

Abstract

Ever since the first biologically active chemokines were discovered in the late 1980s, these messenger proteins and their receptors have been the target for a plethora of drug discovery efforts...

Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2

“…CXCR2-mediated signaling is associated with the pathogenesis of various diseases, including inflammatory diseases affecting the lungs such as chronic obstructive pulmonary disease (COPD) and asthma bronchiale, other inflammatory diseases like ulcerative colitis and psoriasis, and also cancer, thus making CXCR2 a promising target for pharmaceutical intervention. This has prompted intense efforts in the development of small-molecule inhibitors of CXCR2, which are extensively reviewed elsewhere . A selection of high-affinity antagonists ( 1 – 7 ) that are known to bind to the IABS of CXCR2 is shown in Figure .…”

“…2 even progressed to phase II clinical trials for the treatment of several inflammatory diseases, including COPD, asthma, and psoriasis, thus, highlighting the therapeutic potential of intracellular CXCR2 antagonists . However, similar to other clinically tested intracellular CXCR2 antagonists like 6 and 7 , all trials with 2 were terminated after phase II due to limited efficacy . Thus, new approaches to improve the therapeutic efficacy of intracellular CXCR2 antagonism are urgently needed.…”

Small molecules in the treatment of COVID-19

“…In parallel with the growing understanding of the pathogenic mechanisms of SARS-CoV-2 infection, small molecules from natural sources or those produced via chemical synthesis have demonstrated their immense therapeutic potential by intervening with various processes. 13 – 15 The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. In this review, we present a comprehensive overview of the latest progress in the development of small molecule therapeutics for COVID-19 treatment.…”

Small Molecule Tools to Study Cellular Target Engagement for the Intracellular Allosteric Binding Site of GPCRs

“…Vercirnon even progressed to phase III clinical trials for the treatment of Crohn's disease, however, ultimately failed at this late stage of clinical development due to limited therapeutic efficacy, [9] thereby exemplifying the high therapeutic potential but also the current limitations of intracellular GPCR antagonists. The vast majority of the intracellular allosteric GPCR antagonists, which are comprehensively reviewed in the overview articles of Billen et al [10] and Ortiz Zacarías et al, [7] have already been identified and chemically optimized in the absence of any detailed structural information on intracellular GPCR antagonism. The recent disclosure of the co-crystal structures of β 2 AR, [2] CCR2, [3] CCR7, [4] CCR9, [5] CXCR2 [6] in complex with small molecule intracellular antagonists laid the foundation for the structure-based development of further intracellular GPCR antagonists, such as the covalent CCR2 antagonist 7, [11] the dual CCR2/CCR5-antagonist 8, [12] or the CCR9-targeted AAA30 (9, Figure 2).…”

“…Vercirnon even progressed to phase III clinical trials for the treatment of Crohn's disease, however, ultimately failed at this late stage of clinical development due to limited therapeutic efficacy, [9] thereby exemplifying the high therapeutic potential but also the current limitations of intracellular GPCR antagonists. The vast majority of the intracellular allosteric GPCR antagonists, which are comprehensively reviewed in the overview articles of Billen et al [10] . and Ortiz Zacarías et al., [7] have already been identified and chemically optimized in the absence of any detailed structural information on intracellular GPCR antagonism.…”