生物活性

• 描述Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor that mediates the transport of proteins and mRNAs. KPT-330 is a selective inhibitor of CRM1 which shows cytotoxic activity with a median IC₅₀ value of 123 nM in a characterized cell penal with 23 cell lines^[1]. In both STO and MesoII cells, the treatment of 1 μM KPT-330 markedly increased the accumulation of G1phase at 48 hours after the exposure, and reached a maximum at 72 hours. STO cells demonstrated a high sensitivity to KPT-330 with an IC₅₀ of 0.7 μM, whereas MesoII cells with IC₅₀ of 0.35 μM^[2]. KPT-330 at the concentration between 0.1 μM–1 μM induced growth inhibition dose-dependently in eleven NSCLC cell lines. KPT-330 at 1 μM also stimulated the activation of caspase-3 and caspase-9, as well as the protein levels of several pro-apoptotic mediators, including Bax, Bim, and Puma in NSCLC cells. When evaluating the tumor volume of H1975 NSCLC cells engrafted in NOD/SCID mice, KPT-330 treatment (10 mg/kg, twice weekly for 4 weeks) markedly inhibited tumor growth compared with vehicle-treated controls^[3].
• 作用机制KPT-330 inactivates CRM1 by modifying the critical CRM1-binding residue, thereby irreversibly inhibiting CRM1-mediated nuclear export of proteins and mRNAs^[4].

• 动物研究
  剂量	Rat[5]: 0.25 mg/kg - 10 mg/kg (p.o.), 5 mg/kg(i.v.) Monkey[5]: 0.1 mg/kg - 1 mg/kg (p.o.), 2 mg/kg(i.v.) Mice: 3 mg/kg - 30 mg/kg[6] (p.o.)
  给药途径	p.o., i.v.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03110562	Multiple Myeloma	Phase 3	Recruiting	June 2020	-
  NCT02419495	Advanced Malignant Neoplasm ... more >> Recurrent Malignant Neoplasm Refractory Malignant Neoplasm Collapse <<	Phase 1	Recruiting	December 31, 2019	United States, Texas ... more >> M D Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact: Aung Naing    713-563-1930       Principal Investigator: Aung Naing          MD Anderson Regional Care Center-Katy Recruiting Houston, Texas, United States, 77094 Contact: Aung Naing    713-563-1930       Principal Investigator: Aung Naing          MD Anderson Regional Care Center-Bay Area Recruiting Nassau Bay, Texas, United States, 77058 Contact: Aung Naing    713-563-1930       Principal Investigator: Aung Naing          MD Anderson Regional Care Center-Sugar Land Recruiting Sugar Land, Texas, United States, 77478 Contact: Aung Naing    713-563-1930       Principal Investigator: Aung Naing          MD Anderson Regional Care Center-The Woodlands Recruiting The Woodlands, Texas, United States, 77384 Contact: Aung Naing    713-563-1930       Principal Investigator: Aung Naing Collapse <<
  NCT03555422	Endometrial Cancer	Phase 3	Recruiting	January 2021	Belgium ... more >> UZ Leuven Recruiting Leuven, Vlaams-Brabant, Belgium, 3000 Contact: Joke De Roover, PhD    003216347419    joke.deroover@uzleuven.be    Principal Investigator: Ignace Vergote, MD Collapse <<

• 更多
• 参考文献

• [1] Attiyeh EF, Maris JM, et al. Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program. Pediatr Blood Cancer. 2016;63(2):276-86.

  [2] De Cesare M, Cominetti D, et al. Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: the role of survivin. Oncotarget. 2015;6(15):13119-32.

  [3] Sun H, Hattori N, et al. KPT-330 has antitumour activity against non-small cell lung cancer. Br J Cancer. 2014;111(2):281-91.

  [4] https://pubchem.ncbi.nlm.nih.gov/compound/Selinexor#section=Top