6rw2

Bicycle Toxin Conjugate bound to EphA2

spinqualitylabelsall models 6rw2, resolution 2.26Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6rw2 is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.26Å Ligands: 29N, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Bicycles are constrained bicyclic peptides that represent a promising binding modality for use in targeted drug conjugates. A phage display screen against EphA2, a receptor tyrosine kinase highly expressed in a number of solid tumors, identified a number of Bicycle families with low nanomolar affinity. A Bicycle toxin conjugate (BTC) was generated by derivatization of one of these Bicycles with the potent cytotoxin DM1 via a cleavable linker. This BTC demonstrated potent antitumor activity in vivo but was poorly tolerated, which was hypothesized to be the result of undesired liver uptake caused by poor physicochemical properties. Chemical optimization of a second Bicycle, guided by structural biology, provided a high affinity, metabolically stable Bicycle with improved physicochemical properties. A BTC incorporating this Bicycle also demonstrated potent antitumor activity and was very well tolerated when compared to the initial BTC. Phage display selection followed by chemical optimization of Bicycles can deliver potent drug conjugates with favorable pharmaceutical properties. Identification and Optimization of EphA2-Selective Bicycles for the Delivery of Cytotoxic Payloads.,Mudd GE, Brown A, Chen L, van Rietschoten K, Watcham S, Teufel DP, Pavan S, Lani R, Huxley P, Bennett GS J Med Chem. 2020 Apr 2. doi: 10.1021/acs.jmedchem.9b02129. PMID:32202781 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ephrin receptor 3D structures

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