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bioRxiv · 10.1101/2022.12.06.519362

Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma

Liu, H.·Liu, M.·Tian, X.·Wang, H.·Gao, J.·Li, H.·Zhao, Z.·Liu, Y.·Liu, C.·Chen, X.·Yang, Y.
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Abstract

BackgroundThe overactivation of NF-{kappa}B signaling is a key hallmark for the pathogenesis of extranodal natural killer/T cell lymphoma (ENKTL), a very aggressive subtype of non-Hodgkins lymphoma yet with rather limited control strategies. Previously, we found that the dysregulated exportin-1 (also known as CRM1) is mainly responsible for tumor cells to evade apoptosis and promote tumor-associated pathways such as NF-{kappa}B signaling. MethodsHerein we reported the discovery and biological evaluation of a potent small molecule CRM1 inhibitor, LFS-1107. We validated that CRM1 is a major cellular target of LFS-1107 by biolayer interferometry assay (BLI) and the knockdown of CRM1 conferred tumor cells with resistance to LFS-1107. ResultsWe found that LFS-1107 can strongly suppresses the growth of ENKTL cells at low-range nanomolar concentration yet with minimal effects on human platelets and healthy peripheral blood mononuclear cells. Treatment of ENKTL cells with LFS-1107 resulted in the nuclear retention of IkB and consequent strong suppression of NF-{kappa}B transcriptional activities, NF-{kappa}B target genes downregulation and attenuated tumor cell growth and proliferation. Furthermore, LFS-1107 exhibited potent activities when administered to immunodeficient mice engrafted with human ENKTL cells. ConclusionsTherefore, LFS-1107 holds great promise for the treatment of ENKTL and may warrant translation for use in clinical trials.

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Liu, H., Liu, M., Tian, X., Wang, H., Gao, J., Li, H., Zhao, Z., Liu, Y., Liu, C., Chen, X., Yang, Y.. 2022-12-10. Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma. https://doi.org/10.1101/2022.12.06.519362

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