8HUG

F1 in complex with CRM1-Ran-RanBP1

Summary for 8HUG

• Entry DOI: 10.2210/pdb8hug/pdb
• Descriptor: GTP-binding nuclear protein Ran, YRB1 isoform 1, CRM1 isoform 1, ... (10 entities in total)
• Functional Keywords: active ran, complex, transport protein, inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 157690.77

Authors

Sun, Q.,Lei, Y. (deposition date: 2022-12-23, release date: 2023-12-27, Last modification date: 2024-07-10)

Primary citation

Li, C.,Zhang, Q.,Huang, W.,Huang, L.,Long, Q.,Lei, Y.,Jia, D.,Yang, S.,Yang, Y.,Zhang, X.,Sun, Q.
Discovery of a Hidden Pocket beneath the NES Groove by Novel Noncovalent CRM1 Inhibitors.
J.Med.Chem., 66:17044-17058, 2023

PubMed Abstract: Protein localization is frequently manipulated to favor tumor initiation and progression. In cancer cells, the nuclear export factor CRM1 is often overexpressed and aberrantly localizes many tumor suppressors via protein-protein interactions. Although targeting protein-protein interactions is usually challenging, covalent inhibitors, including the FDA-approved drug KPT-330 (selinexor), were successfully developed. The development of noncovalent CRM1 inhibitors remains scarce. Here, by shifting the side chain of two methionine residues and virtually screening against a large compound library, we successfully identified a series of noncovalent CRM1 inhibitors with a stable scaffold. Crystal structures of inhibitor-protein complexes revealed that one of the compounds, B28, utilized a deeply hidden protein interior cavity for binding. SAR analysis guided the development of several B28 derivatives with enhanced inhibition on nuclear export and growth of multiple cancer cell lines. This work may benefit the development of new CRM1-targeted therapies.

PubMed: 38105606
DOI: 10.1021/acs.jmedchem.3c01867

Experimental method

X-RAY DIFFRACTION (2.15 Å)