6tg1

Crystal Structure of EGFR T790M/V948R in Complex with Covalent Pyrrolopyrimidine 21b

spinqualitylabelsall models 6tg1, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: EDO, N82, NA, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Mutated or amplified Her2 serves as a driver of non-small cell lung cancer (NSCLC) or mediates resistance toward the inhibition of its family member EGFR (epidermal growth factor receptor) with small-molecule inhibitors. Current data from clinical candidates revealed that inhibitors targeting Her2 suffer from poor response rates of less than 40%, and therefore, the development of novel inhibitors was undertaken. In this study, the well-established pyrrolopyrimidine scaffold was modified with structural motifs identified from a screening campaign with more than 1600 compounds which were applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA. The resulting inhibitors were designed to covalently target a reactive cysteine in the binding site of Her2 and were further optimized by means of structure-based drug design utilizing a set of obtained complex crystal structures. In addition, the analysis of binding kinetics and absorption, distribution, metabolism, and excretion (ADME) parameters, as well as MS experiments and western blot analysis substantiated our approach. Targeting Her2-insYVMA with Covalent Inhibitors - A Focused Compound Screening and Structure-Based Design Approach.,Lategahn J, Hardick J, Grabe T, Niggenaber J, Jeyakumar K, Keul M, Tumbrink HL, Becker C, Hodson L, Kirschner T, Klovekorn P, Ketzer J, Baumann M, Terheyden S, Unger A, Weisner J, Muller MP, van Otterlo WAL, Bauer S, Rauh D J Med Chem. 2020 Sep 15. doi: 10.1021/acs.jmedchem.0c00870. PMID:32931277 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Epidermal growth factor receptor 3D structures

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