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Discovery of Aminor...
Discovery of Aminoratjadone Derivatives as Potent Noncovalent CRM1 Inhibitors
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Jian, L. A. (författare)
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Zscherp, R. (författare)
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Beutling, U. (författare)
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Shen, X. F. (författare)
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Xu, S. Y. (författare)
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Zhang, X. (författare)
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Bronstrup, M. (författare)
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- Klahn, Philipp (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Sun, Q. X. (författare)
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(creator_code:org_t)
- 2023
- 2023
- Engelska.
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Ingår i: Journal of Medicinal Chemistry. - 0022-2623. ; 66:17, s. 11940-50
- Relaterad länk:
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Cancer cells frequently utilize elevated nuclear exportto escapetumor suppression and gain proliferative advantage. Chromosome RegionMaintenance 1 (CRM1/XPO1) mediates macromolecule nuclear export andplays an important role in tumorigenesis and progression. The clinicalapproval of its covalent inhibitor KPT-330 (Selinexor) validates thefeasibility of targeting CRM1 to treat cancers. Here, we synthesizedfour aminoratjadone derivatives and found that two of them, KL1 and KL2, are noncovalent CRM1 inhibitors.The two compounds underwent spontaneous hydrolysis in aqueous buffers,and the resulting products were more active against CRM1. High-resolutioncrystal structures revealed the CRM1-binding mode of these compoundsand explained the observed structure-activity relationships.In cells, KL1 and KL2 localized CRM1 inthe nuclear periphery and led to depletion of nuclear CRM1, therebyinhibiting the nuclear export and growth of colorectal cancer cellsat submicromolar concentrations. This work lays the foundation forfurther development of aminoratjadone-based noncovalent CRM1 inhibitors.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Nyckelord
- nuclear export
- leptomycin b
- covalent
- degradation
- design
- cells
- Pharmacology & Pharmacy
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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