Suppression of HDAC nuclear export and cardiomyocyte hypertrophy by novel irreversible inhibitors of CRM1

Monovich, Lauren G.; Koch, Keith A.; Burgis, Robin; Osimboni, Ekundayo; Mann, Thierry; Wall, Daniel; Gao, Jin; Yan, Feng; Vega, Richard B.; Turner, Benjamin A.; Hood, David B.; Law, Andy; Papst, Philip J.; Koditek, David; Chapo, Joseph; Reid, Brian G.; Melvin, Lawrence S.; Pagratis, Nikos; McKinsey, Timothy A.

doi:10.1016/j.bbagrm.2009.04.001

Cited by 30 publications

(27 citation statements)

References 23 publications

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“…by guest www.bloodjournal.org From offers an explanation for the reduced efficiency of CBS9106 versus LMB in competitive pull-down assays ( Figure 5B). Whereas CBS9106 and most other CRM1 inhibitors target Cys528 of CRM1, [12][13][14][15][16][17][18] to the best of our knowledge, only CBS9106 induces CRM1 depletion via the ubiquitin/proteasome pathway ( Figures 4B and 5A). This CBS9106-induced CRM1 depletion was suppressed in the presence of LMB (Figure 5A), suggesting that binding to Cys528 of CRM1 is indispensable for CBS9106-induced CRM1 depletion.…”

Section: Discussionmentioning

confidence: 99%

“…2,3,[8][9][10] A well-known CRM1-specific inhibitor, leptomycin B (LMB), binds covalently to Cys528 of CRM1 by a Michael-type addition reaction and abrogates the interaction between CRM1 and its cargo protein. 2,3,11 In addition, other CRM1 inhibitors, which have structures that are either similar to LMB [12][13][14] or apparently different, [15][16][17][18] also target Cys528 of CRM1. LMB shows high antitumor activity against a broad range of cancer cell lines in vitro (IC 50 values in 0.1-10nM range).…”

Section: Introductionmentioning

confidence: 99%

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

Sakakibara¹,

Saito²,

Sato³

et al. 2011

Blood

114

115

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CRM1 plays an important role in the nuclear export of cargo proteins bearing nuclear exporting signal sequences. Leptomycin B (LMB), a well-known CRM1 inhibitor, possesses strong antitumor properties. However, its toxicity prevents it from being clinically useful. In this study, we demonstrate that a novel compound, CBS9106, inhibits CRM1-dependent nuclear export, causing arrest of the cell cycle and inducing apoptosis in a time-and dose-dependent manner for

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sakakibara¹,

Saito²,

Sato³

et al. 2011

Blood

114

115

View full text Add to dashboard Cite

show abstract

“…A phase I clinical trial, however, showed large dose-dependent toxicity deeming LMB unsuitable for clinical use [111]. In attempts to reduce potential off-target effects of LMB, several modified versions of LMB were studied and reported to have improved pharmacological properties [112, 113]. …”

Section: A Summary Of Crm1 Structuresmentioning

confidence: 99%

Atomic basis of CRM1-cargo recognition, release and inhibition

Fung

Chook

2014

Seminars in Cancer Biology

135

124

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CRM1 or XPO1 is the major nuclear export receptor in the cell, which controls the nuclear-cytoplasmic localization of many proteins and RNAs. CRM1 is also a promising cancer drug target as the transport receptor is overexpressed in many cancers and quite a few of its cargos are misregulated in the diseases and hence mislocalized to the cytoplasm. Atomic level understanding of CRM1 function has greatly facilitated recent drug discovery and development of CRM1 inhibitors to target a variety of malignancies. Numerous atomic resolution CRM1 structures are now available, explaining how the exporter recognizes nuclear export signals in its cargos, how RanGTP and cargo bind with positive cooperativity, how RanBP1 causes release of export cargos in the cytoplasm and how diverse inhibitors such as Leptomycin B and the new KPT-SINE compounds block nuclear export. This review summarizes the structure-function studies that explain CRM1-cargo recognition, release and inhibition.

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“…[55] A similar set of α,β-unsaturated amides was identified by a Novartis group in 2009. [56] A sophisticated high content screen for inhibitors of HDAC nuclear export of > 15 the hit compound revealed that an impurity caused the positive signal, and it was shown that α,β-unsaturated diamide 23 was the active compound. This compound resulted in a 2.2 nM concentration for successful inhibition of HDAC5 nuclear export.…”

Section: Small Molecule Inhibitors Of Nuclear Exportmentioning

confidence: 99%

Controlling Protein Transport by Small Molecules

Gademann

2011

CDT

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Many proteins are transported from the nucleus to the cytoplasm by the exportin CRM1, which recognizes cargo proteins through a leucine rich nuclear export signal (NES). This nuclear export process can be inhibited by several small molecules, both natural products and fully synthetic compounds. The structural basis for the inhibition of nuclear export by leptomycin (LMB) based on disruption of the protein/protein interaction between CRM1 and cargo proteins is discussed. The chemistry and inhibition of nucleocytoplasmic transport of leptomycin, anguinomycin and derivatives, goniothalamin, JBIR-02, valtrate, dihydrovaltrate, ACA, peumusolide A and several synthetic compounds is presented. Consequences for the design of nuclear export inhibitors is discussed, and the potential of these compounds as anticancer agents is evaluated.

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Suppression of HDAC nuclear export and cardiomyocyte hypertrophy by novel irreversible inhibitors of CRM1

Cited by 30 publications

References 23 publications

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

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

Atomic basis of CRM1-cargo recognition, release and inhibition

Controlling Protein Transport by Small Molecules

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