GSK2239633 / GSK - LARVOL DELTA

Structure basis for C-C chemokine receptor 4 modulation by orthosteric and allosteric antagonists. (PubMed, Proc Natl Acad Sci U S A) - "Tivumecirnon (FLX475) and Zelnecirnon (RPT193), two clinical-stage investigational drugs, bind to the orthosteric site of CCR4, blocking the chemokine recognition site 1. In contrast, AZD2098 and GSK2239633A occupy an allosteric site near the TM7-H8 turn, presumably interfering with G-protein coupling. Further analyses reveal that the therapeutic antibody mogamulizumab binds to the N-terminal region of CCR4 without competing with CCL17, suggesting that its antagonistic effect is mediated exclusively through antibody-dependent cellular cytotoxicity. Together, these structural insights elucidate distinct modes of CCR4 inhibition and provide a framework for the rational design of next-generation therapeutics targeting chemokine receptors."

Journal • Adult T-Cell Leukemia-Lymphoma • Cutaneous T-cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CCL2 • CCL22 • CCR4

Exploring an Intracellular Allosteric Site of CC-Chemokine Receptor 4 from 3D Models, Probe Simulations, and Mutagenesis. (PubMed, ACS Pharmacol Transl Sci) - "We applied our previously developed probe confined dynamic mapping protocol, which combines enhanced sampling molecular dynamics (MD) simulations and fragment-based approaches, to identify the binding site of GSK2239633A (N-[[3-[[3-[(5-chlorothiophen-2-yl)sulfonylamino]-4-methoxyindazol-1-yl]methyl]phenyl]methyl]-2-hydroxy-2-methylpropanamide), a selective CC-chemokine receptor type 4 (CCR4) negative allosteric modulator, using CCR4 homology and AlphaFold models...Further analysis of 3D models and MD simulations highlighted the pair of residues 6.36 and 7.56 that might account for antagonist selectivity among chemokine receptors. Our in silico protocol provides a promising approach for characterizing ligand binding sites in membrane proteins, considering receptor dynamics and adaptability and guiding protein template selection for ligand design."

Journal • CCR4