A low toxic CRM1 degrader: Synthesis and anti-proliferation on MGC803 and HGC27

Xu, Haiwei; Jia, Shilong; Liu, Mengbo; Li, Xiaobo; Meng, Xin; Wu, Xinxin; Yu, Lu‐Gang; Wang, Menglin; Jin, Cheng‐Yun

doi:10.1016/j.ejmech.2020.112708

Cited by 6 publications

(2 citation statements)

References 23 publications

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“…Previously, leptomycine B (LMB) and a goniothalamin-derived covalent inhibitor inhibited the growth of the human gastric carcinoma cell line HGC27 at tens of nanomolar and tens of micromolar concentrations, respectively. 20,21 Taking HGC27 as an example, it was found that 1, 2, 3, and 4 displayed similar half-maximal inhibitory concentrations (IC 50 44−63 μM), but 5 and 6 were much less active (Figure 5A, IC 50 285 and 457 μM). Furthermore, 1 but not 5 increased the thermal stability of CRM1 in a cellular thermal shift assay (CESTA, Figure 5B).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach

et al. 2023

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Chromosomal region maintenance protein 1 (CRM1) is a validated anticancer drug target, and its covalent inhibitor KPT-330 has been approved for marketing. However, the development of CRM1 inhibitors, especially the noncovalent ones, is still very limited. Drug repurposing is an effective strategy to develop drug leads for new targets. In this work, we virtually screened a library of marketed drugs and identified zafirlukast as a new CRM1 inhibitor. Biochemical and structural analysis revealed that zafirlukast was a noncovalent CRM1 inhibitor that bound to four subpockets in the nuclear-export-signal (NES) groove. Methylation of the sulfonamide group rendered zafirlukast completely inactive against CRM1. Zafirlukast inhibited the growth of a variety of cancer cells and worked synergistically with the drug doxorubicin. Taken together, these works laid a solid foundation for reshaping zafirlukast as a valuable lead compound for further design of noncovalent, specific, and potent CRM1 inhibitors toward the treatment of various cancers.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach

et al. 2023

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“…(R)-6-[(2-isopropyl-5-methylphenoxy) methyl]-5,6-dihydro-2-Pyron (compound 11) is a colourless oily liquid. The cytotoxic effects of compound 1l in HGC27 and MGC803 gastric cancer cell lines have been investigated; compound 1l was reported to degrade XPO1, inducing apoptosis in both MGC803 and HGC27 cell lines, exhibiting strong cytotoxic and anti-tumour effects against these cells ( 104 ).…”

Section: Inhibitors Of Xpo1mentioning

confidence: 99%

Targeting of nucleo‑cytoplasmic transport factor exportin 1 in malignancy

Özdaş

Canatar

2021

Med Int

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Nuclear pore complexes (NPCs) regulate the entry and exit of molecules from the cell nucleus. Small molecules pass through NPCs by diffusion while large molecules enter and exit the nucleus by karyopherins, which serve as transport factors. Exportin-1 (XPo1) is a protein that is an important member of the karyopherin family and carries macromolecules from the nucleus to the cytoplasm. XPo1 is responsible for nuclear-cytoplasmic transport of protein, ribosomal rNa and certain required mrNas for ribosomal biogenesis. Furthermore, XPo1-mediated nuclear export is associated with various types of disease, such as cancer, inflammation and viral infection. the key role of XPo1 in carcinogenesis and its potential as a therapeutic target has been demonstrated by previous studies. Clinical use of novel developed generation-specific XPO1 inhibitors and their combination with other agents to block XPo1-mediated nuclear export are a promising new treatment strategy. the aim of the present study was to explain the working mechanism of XPo1 and inhibitors that block XPo1-mediated nuclear export. Contents 1. Nucleo-cytoplasmic transport 2. Structure of XPo1 3. Physiological function of XPo1 in cells 4. XPo1 export of protein 5. Single nucleotide polymorphisms (SNPs) of XPo1 6. XPo1 in cancer 7. Inhibitors of XPo1 8. Conclusion and future directions

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Pd/Et₃N·HI-Catalyzed Intramolecular C–H Alkylation to Access [a]-Annulated Indoles via Highly Regioselective Ring-Opening of Epoxides

Sun

Yang

et al. 2022

J. Org. Chem.

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A Pd/Et 3 N•HI-catalyzed intramolecular C−H alkylation of indoles with epoxides was achieved to furnish Nfused indole frameworks (5-, 6-, and 7-membered rings) bearing an alcohol group. The conversion proceeded smoothly in the presence of a catalytic amount of Et 3 N•HI together with a palladium catalyst and exhibited great functional group tolerance. The employment of Et 3 N•HI not only avoids the prior preparation of alkyl halide substrates but also is the key to the high chemoselective ringopening of epoxides. Preliminary mechanism explorations strongly support a radical pathway, and the catalytic cycle was established tentatively according to the mechanism investigation experiments.

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A low toxic CRM1 degrader: Synthesis and anti-proliferation on MGC803 and HGC27

Cited by 6 publications

References 23 publications

Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach

Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach

Targeting of nucleo‑cytoplasmic transport factor exportin 1 in malignancy

Pd/Et₃N·HI-Catalyzed Intramolecular C–H Alkylation to Access [a]-Annulated Indoles via Highly Regioselective Ring-Opening of Epoxides

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A low toxic CRM1 degrader: Synthesis and anti-proliferation on MGC803 and HGC27

Cited by 6 publications

References 23 publications

Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach

Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach

Targeting of nucleo‑cytoplasmic transport factor exportin 1 in malignancy

Pd/Et3N·HI-Catalyzed Intramolecular C–H Alkylation to Access [a]-Annulated Indoles via Highly Regioselective Ring-Opening of Epoxides

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Pd/Et₃N·HI-Catalyzed Intramolecular C–H Alkylation to Access [a]-Annulated Indoles via Highly Regioselective Ring-Opening of Epoxides