6RW2

Bicycle Toxin Conjugate bound to EphA2

6RW2 の概要

• エントリーDOI: 10.2210/pdb6rw2/pdb
• 分子名称: Ephrin type-A receptor 2, ALA-ARG-ASP-CYS-PRO-LEU-VAL-ASN-PRO-LEU-CYS-LEU-HIS-PRO-GLY-TRP-THR-CYS, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: epha2, inhibitor, complex, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 24351.47

構造登録者

Brown, D.G.,Schroeder, S.,Chen, L. (登録日: 2019-06-03, 公開日: 2020-04-08, 最終更新日: 2024-10-16)

主引用文献

Mudd, G.E.,Brown, A.,Chen, L.,van Rietschoten, K.,Watcham, S.,Teufel, D.P.,Pavan, S.,Lani, R.,Huxley, P.,Bennett, G.S.
Identification and Optimization of EphA2-Selective Bicycles for the Delivery of Cytotoxic Payloads.
J.Med.Chem., 63:4107-4116, 2020

PubMed Abstract: 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 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.

PubMed: 32202781
DOI: 10.1021/acs.jmedchem.9b02129

実験手法

X-RAY DIFFRACTION (2.26 Å)