AI Article Synopsis
- Cancer cells often trick the body by moving important proteins, like tumor suppressors, to the wrong places, which helps the cancer grow.
- Scientists found a way to make new medicines that can stop one of the proteins helping this process, called CRM1.
- One of the new medicines, called B28, works really well by fitting into a special part of the CRM1 protein, and it could help create better treatments for cancer.
Article 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.
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| http://dx.doi.org/10.1021/acs.jmedchem.3c01867 | DOI Listing |
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