6AY2

Structure of CathB with covalently linked Compound 28

6AY2 の概要

• エントリーDOI: 10.2210/pdb6ay2/pdb
• 分子名称: Cathepsin B, N~1~-[(2S)-1-amino-5-(carbamoylamino)pentan-2-yl]-N'~1~-[(1R)-1-(thiophen-3-yl)ethyl]cyclobutane-1,1-dicarboxamide (3 entities in total)
• 機能のキーワード: protease, covalent, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Lysosome : P07858
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 56735.35

構造登録者

Kiefer, J.R.,Steinbacher, S. (登録日: 2017-09-07, 公開日: 2017-12-27, 最終更新日: 2024-10-16)

主引用文献

Wei, B.,Gunzner-Toste, J.,Yao, H.,Wang, T.,Wang, J.,Xu, Z.,Chen, J.,Wai, J.,Nonomiya, J.,Tsai, S.P.,Chuh, J.,Kozak, K.R.,Liu, Y.,Yu, S.F.,Lau, J.,Li, G.,Phillips, G.D.,Leipold, D.,Kamath, A.,Su, D.,Xu, K.,Eigenbrot, C.,Steinbacher, S.,Ohri, R.,Raab, H.,Staben, L.R.,Zhao, G.,Flygare, J.A.,Pillow, T.H.,Verma, V.,Masterson, L.A.,Howard, P.W.,Safina, B.
Discovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity.
J. Med. Chem., 61:989-1000, 2018

PubMed Abstract: Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine-citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs.

PubMed: 29227683
DOI: 10.1021/acs.jmedchem.7b01430

実験手法

X-RAY DIFFRACTION (1.6 Å)