Publications by authors named "David F Yan"

Covalent drug discovery has experienced a renaissance, with numerous electrophilic small molecules recently gaining FDA approval. Many structurally diverse electrophilic small molecules target exportin-1 (XPO1/CRM1) at cysteine 528, including the selective inhibitor of nuclear export (SINE) selinexor, which was FDA-approved as an anticancer agent in 2019. Emerging evidence supports additional pharmacological classes of XPO1 modulators targeting Cys528, including the selective inhibitors of transcriptional activation (SITAs) and probes that induce rapid degradation of XPO1.

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Article Synopsis
  • Exportin-1 (XPO1) is crucial for transporting proteins from the nucleus to the cytoplasm and also plays a role in processes like centrosome duplication; it is targeted by small molecules for cancer treatment, notably selinexor for multiple myeloma.
  • Research highlights a cell-type-dependent function of XPO1 in binding to chromatin, which is vital for the activity of NFAT transcription factors and proper T cell activation.
  • A new class of XPO1-targeting small molecules has been developed that disrupt XPO1's chromatin binding specifically, providing a potential therapeutic avenue for treating T cell-driven autoimmune disorders without causing cell death.
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Cancer cell culture models frequently rely on fetal bovine serum as a source of protein and lipid factors that support cell survival and proliferation; however, serum-containing media imperfectly mimic the in vivo cancer environment. Recent studies suggest that typical serum-containing cell culture conditions can mask cancer dependencies, for example, on cholesterol biosynthesis enzymes, that exist in vivo and emerge when cells are cultured in media that provide more realistic levels of lipids. Here, we describe a high-throughput screen that identified fenretinide and ivermectin as small molecules whose cytotoxicity is greatly enhanced in lipid-restricted media formulations.

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