CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity

Sakakibara, Kazutoshi; Saito, Naoya; Sato, Takuji; Suzuki, Atsushi; Hirabayashi, Yoko; Friedman, Jonathan M.; Küfe, Donald; VonHoff, Daniel D.; Iwami, Tadahiko; Kawabe, Takumi

doi:10.1182/blood-2011-01-333138

Cited by 109 publications

(122 citation statements)

References 35 publications

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“…All these compounds inhibit XPO1 by binding its C528 residue, causing cell-cycle arrest and apoptosis in a time-and dose-dependent manner in a broad spectrum of cancer cells. These inhibitors are more clinically relevant because they are much less toxic than LMB, while maintaining high potency (46)(47)(48).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Conforti

Wang

Rodriguez

et al. 2015

Clinical Cancer Research

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A dynamic distribution between nucleus and cytoplasm (nucleocytoplasmic shuttling) is one of the control mechanisms adapted by normal cells to regulate the activity of a variety of molecules. Growing evidence suggests that dysregulation of the nucleocytoplasmic shuttling is involved in promoting abnormal cell survival, tumor progression, and drug resistance, and is associated with poor cancer prognosis. Aberrant nucleocytoplasmic shuttling in cancer cells may result from a hyperactive status of diverse signal-transduction pathways, such as the PI3K-AKT and MAPK pathways, or from alterations in the general nuclear import/export machinery. Among the large number of molecules involved in the shuttling process, exportin XPO1, also known as chromosome region maintenance 1, appears to play a particularly prominent role in pathogenesis of both hematological malignancies and solid tumors. Given the importance of nucleocytoplasmic shuttling in cancer pathogenesis and the rapidly expanding knowledge in this field, attempts have been made to develop compounds able to revert the aberrant nucleocytoplasmic shuttling. A promising new drug, , which belongs to the class of XPO1 inhibitors called selective inhibitors of nuclear export, is now being tested in phase I/II clinical trials.

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Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Conforti

Wang

Rodriguez

et al. 2015

Clinical Cancer Research

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“…covalent bond with it and was found to inhibit tumor growth in xenograft models without signifi cant weight loss or mortality ( 70 ). Both of these compounds have not progressed into the clinic but are at least indicative that XPO1 can be inhibited with an adequate therapeutic window.…”

Section: Reviewmentioning

confidence: 99%

“…Signifi cantly better tolerability and less weight loss than with Leptomycin-B were observed in animals, although transient anorexia remained ( 69 ). More recently, a small-molecule reversible inhibitor of XPO1, CBS9106, which induced cell-cycle arrest and apoptosis as a single agent in 60 different human cancer cell lines, including bladder, breast, colon, and lung cancer, at submicromolar concentrations has been described ( 70 …”

Section: Synthetic Xpo1 Inhibitorsmentioning

confidence: 99%

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

et al. 2014

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In cancer cells, the nuclear-cytoplasmic transport machinery is frequently disrupted, resulting in mislocalization and loss of function for many key regulatory proteins. In this review, the mechanisms by which tumor cells co-opt the nuclear transport machinery to facilitate carcinogenesis, cell survival, drug resistance, and tumor progression will be elucidated, with a particular focus on the role of the nuclear-cytoplasmic export protein. The recent development of a new generation of selective inhibitors of nuclear export (XPO1 antagonists) and how these novel anticancer drugs may bring us closer to the implementation of this therapeutic strategy in the clinic will be discussed. Signifi cance:The nuclear transport mechanism is dysregulated in many malignancies and is associated with dysfunction of many regulatory proteins. Targeting this mechanism as an anticancer strategy has been compelling, and novel agents that selectively inhibit the nuclear export pathway have demonstrated preliminary evidence of clinical effi cacy with an acceptable safety profi le. Cancer Discov; 4(5); 527-37.

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“…Furthermore, CBS9106, a novel reversible CRM1 inhibitor, was recently identified and reported to have anti-tumor activity against multiple myeloma. 23 However, the effect of CRM1 inhibitors on colorectal cancer cell growth in vitro has not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

Novel reversible selective inhibitor of nuclear export shows that CRM1 is a target in colorectal cancer cells

Niu

Chong

Han

et al. 2015

Cancer Biology & Therapy

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Abbreviations: CRM1, chromosomal region maintenance 1; DMSO, dimethyl sulfoxide; EGFR, epidermal growth factor receptor; LMB, leptomycin B; NES, leucine-rich nuclear export signal; PI3K, phosphoinositide 3-kinase; RanBP1, Ran-binding protein 1.Colorectal cancer arises via a multistep carcinogenic process and the deregulation of multiple pathways. Thus, the simultaneous targeting of multiple pathways may be a promising therapeutic approach for colorectal treatment. CRM1 is an attractive cancer drug target, because it can regulate multiple pathways and tumor suppressor proteins. In this study, we investigated the anti-tumor activity of a novel reversible CRM1 inhibitor S109 in colorectal cancer. Our data demonstrate that S109 inhibits proliferation and induces cell cycle arrest in colorectal cancer cells. Mechanistically, we demonstrate that the activity of S109 is associated with the nuclear retention of major tumor suppress proteins. Furthermore, the Cys528 mutation of CRM1 prevented the ability of S109 to block nuclear export and inhibit the proliferation of colorectal cancer cells. Interestingly, S109 decreased the CRM1 protein level via proteasomal pathway. We argue that reversible CRM1 inhibitors but not irreversible inhibitors can induce the degradation of CRM1, because the dissociation of reversible inhibitors of CRM1 changes the conformation of CRM1. Taken together, these findings demonstrate that CRM1 is a valid target for the treatment of colorectal cancer and provide a basis for the development of S109 therapies for colorectal cancer.

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CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity

Cited by 109 publications

References 35 publications

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

Novel reversible selective inhibitor of nuclear export shows that CRM1 is a target in colorectal cancer cells

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