6CW8

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with RTS-V5

6CW8 の概要

• エントリーDOI: 10.2210/pdb6cw8/pdb
• 分子名称: Hdac6 protein, ZINC ION, POTASSIUM ION, ... (6 entities in total)
• 機能のキーワード: histone deacetylase, metallohydrolase, hydrolase
• 由来する生物種: Danio rerio (Zebrafish)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82467.98

構造登録者

Osko, J.D.,Christianson, D.W. (登録日: 2018-03-30, 公開日: 2018-11-21, 最終更新日: 2023-10-04)

主引用文献

Bhatia, S.,Krieger, V.,Groll, M.,Osko, J.D.,Ahlert, H.,Borkhardt, A.,Kurz, T.,Christianson, D.W.,Hauer, J.,Hansen, F.K.
Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor.
J. Med. Chem., 61:10299-10309, 2018

PubMed Abstract: Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with leukemia and multiple myeloma cell lines as well as therapy refractory primary patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and selective anticancer activity. Our results will thus guide the structure-based optimization of dual HDAC-proteasome inhibitors for the treatment of hematological malignancies.

PubMed: 30365892
DOI: 10.1021/acs.jmedchem.8b01487

実験手法

X-RAY DIFFRACTION (1.9 Å)