8HQ3

KL1 in complex with CRM1-Ran-RanBP1

Summary for 8HQ3

• Entry DOI: 10.2210/pdb8hq3/pdb
• Descriptor: GTP-binding nuclear protein Ran, methyl (3~{S},5~{R},6~{E},8~{Z},10~{R},12~{E},14~{E},16~{R})-3,16-bis(azanyl)-8,10,12-trimethyl-16-[(2~{S},4~{R},5~{S},6~{S})-5-methyl-4-oxidanyl-6-[(~{E})-prop-1-enyl]oxan-2-yl]-5-oxidanyl-hexadeca-6,8,12,14-tetraenoate, YRB1 isoform 1, ... (11 entities in total)
• Functional Keywords: nuclear export inhibitor, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 159185.42

Authors

Sun, Q.,Jian, L. (deposition date: 2022-12-13, release date: 2023-10-25)

Primary citation

Jian, L.,Zscherp, R.,Beutling, U.,Shen, X.,Xu, S.,Zhang, X.,Bronstrup, M.,Klahn, P.,Sun, Q.
Discovery of Aminoratjadone Derivatives as Potent Noncovalent CRM1 Inhibitors.
J.Med.Chem., 66:11940-11950, 2023

PubMed Abstract: Cancer cells frequently utilize elevated nuclear export to escape tumor suppression and gain proliferative advantage. Chromosome Region Maintenance 1 (CRM1/XPO1) mediates macromolecule nuclear export and plays an important role in tumorigenesis and progression. The clinical approval of its covalent inhibitor KPT-330 (Selinexor) validates the feasibility of targeting CRM1 to treat cancers. Here, we synthesized four aminoratjadone derivatives and found that two of them, and , are noncovalent CRM1 inhibitors. The two compounds underwent spontaneous hydrolysis in aqueous buffers, and the resulting products were more active against CRM1. High-resolution crystal structures revealed the CRM1-binding mode of these compounds and explained the observed structure-activity relationships. In cells, and localized CRM1 in the nuclear periphery and led to depletion of nuclear CRM1, thereby inhibiting the nuclear export and growth of colorectal cancer cells at submicromolar concentrations. This work lays the foundation for further development of aminoratjadone-based noncovalent CRM1 inhibitors.

PubMed: 37595020
DOI: 10.1021/acs.jmedchem.3c00549

Experimental method

X-RAY DIFFRACTION (2.1 Å)