Delving into the Latest Updates on Cmp2105 with Synapse

A review.Conventional drug discovery against GPCRs has typically focused on extracellular orthosteric and allosteric binding pockets.Crystal structure of CCR7 in complex with Cmp2105, an intracellular allosteric antagonist, expands the emerging framework of targeting intracellular allosteric pockets on GPCRs.

01 Aug 2019·CellQ1 · BIOLOGY

Structural Basis for Allosteric Ligand Recognition in the Human CC Chemokine Receptor 7

Q1 · BIOLOGY

Article

Author: Joerg Standfuss ; Markus G. Rudolph ; Jean-Marie Vonach ; Martin Weber ; Wolfgang Guba ; Alain Gast ; Noemi Haenggi ; Antonia Furrer ; Steffen Bruenle ; Takuya Miyazaki ; Tobias Weinert ; Daniel Mattle ; Chia-Ying Huang ; Tim Tetaz ; Kathrin Jaeger ; Joerg Benz ; Przemyslaw Nogly ; Andreas Kuglstatter ; Roger J.P. Dawson ; Jonas Muehle

The CC chemokine receptor 7 (CCR7) balances immunity and tolerance by homeostatic trafficking of immune cells. In cancer, CCR7-mediated trafficking leads to lymph node metastasis, suggesting the receptor as a promising therapeutic target. Here, we present the crystal structure of human CCR7 fused to the protein Sialidase NanA by using data up to 2.1 Å resolution. The structure shows the ligand Cmp2105 bound to an intracellular allosteric binding pocket. A sulfonamide group, characteristic for various chemokine receptor ligands, binds to a patch of conserved residues in the Gi protein binding region between transmembrane helix 7 and helix 8. We demonstrate how structural data can be used in combination with a compound repository and automated thermal stability screening to identify and modulate allosteric chemokine receptor antagonists. We detect both novel (CS-1 and CS-2) and clinically relevant (CXCR1-CXCR2 phase-II antagonist Navarixin) CCR7 modulators with implications for multi-target strategies against cancer.

100 Deals associated with Cmp2105

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