6AY2

Structure of CathB with covalently linked Compound 28

Summary for 6AY2

• Entry DOI: 10.2210/pdb6ay2/pdb
• Descriptor: 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)
• Functional Keywords: protease, covalent, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Lysosome : P07858
• Total number of polymer chains: 2
• Total formula weight: 56735.35

Authors

Kiefer, J.R.,Steinbacher, S. (deposition date: 2017-09-07, release date: 2017-12-27, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.6 Å)